Macrocycles as factor XIa inhibitors

ABSTRACT

The present invention provides compounds of Formula (I): 
                         
or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein all the variables are as defined herein. These compounds are selective Factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

CROSS REFERENCE TO RELATED APPLICATIONS

This Divisional application claims the benefit of U.S. Ser. No.14/578,846 5 filed filed Dec. 22, 2014, now U.S. Pat No. 9,802,939,which is a Divisional of U.S. Ser. No. 13/024,544 filed Feb. 10, 2011,now U.S. Pat. No. 8,940,720, which in turn claims the benefit of U.S.Provisional Application Ser. No. 61/303,423 filed Feb. 11, 2010 and U.S.Provisional Application Ser. No. 61/405,338 filed Oct. 21, 2010, herebyincorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates generally to novel macrocyclic compounds,and their analogues thereof, which are inhibitors of Factor XIa and/orplasma kallikrein, compositions containing them, and methods of usingthem, for example, for the treatment or prophylaxis of thromboembolicdisorders.

BACKGROUND OF THE INVENTION

Thromboembolic diseases remain the leading cause of death in developedcountries despite the availability of anticoagulants such as warfarin(COUMADIN®), heparin, low molecular weight heparins (LMWH), andsynthetic pentasaccharides and antiplatelet agents such as aspirin andclopidogrel (PLAVIX®). The oral anticoagulant warfarin, inhibits thepost-translational maturation of coagulation Factors VII, IX, X andprothrombin, and has proven effective in both venous and arterialthrombosis. However, its usage is limited due to its narrow therapeuticindex, slow onset of therapeutic effect, numerous dietary and druginteractions, and a need for monitoring and dose adjustment. Thus,discovering and developing safe and efficacious oral anticoagulants forthe prevention and treatment of a wide range of thromboembolic disordershas become increasingly important.

One approach is to inhibit thrombin generation by targeting theinhibition of coagulation Factor XIa (FXIa). Factor XIa is a plasmaserine protease involved in the regulation of blood coagulation, whichis initiated in vivo by the binding of tissue factor (TF) to Factor VII(FVII) to generate Factor VIIa (FVIIa). The resulting TF:FVIIa complexactivates Factor IX (FIX) and Factor X (FX) that leads to the productionof Factor Xa (FXa). The generated FXa catalyzes the transformation ofprothrombin into small amounts of thrombin before this pathway is shutdown by tissue factor pathway inhibitor (TFPI). The process ofcoagulation is then further propagated via the feedback activation ofFactors V, VIII and XI by catalytic amounts of thrombin. (Gailani, D. etal., Arterioscler. Thromb. Vasc. Biol., 27:2507-2513 (2007).) Theresulting burst of thrombin converts fibrinogen to fibrin thatpolymerizes to form the structural framework of a blood clot, andactivates platelets, which are a key cellular component of coagulation(Hoffman, M., Blood Reviews, 17:S1-S5 (2003)). Therefore, Factor XIaplays a key role in propagating this amplification loop and is thus anattractive target for anti-thrombotic therapy.

SUMMARY OF THE INVENTION

The present invention provides novel macrocyclic compounds, theiranalogues, including stereoisomers, tautomers, pharmaceuticallyacceptable salts, or solvates thereof, which are useful as selectiveinhibitors of serine protease enzymes, especially Factor XIa and/orplasma kallikrein.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of thromboembolic disorders.

The compounds of the present invention may be used in therapy.

The compounds of the present invention may be used for the manufactureof a medicament for the treatment and/or prophylaxis of a thromboembolicdisorder.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore, preferably one to two other agent(s).

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION

I. Compounds of the Invention

In a first aspect, the present invention provides, inter alia, acompound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, wherein:

ring A is independently a C₃₋₁₀ carbocycle or a 5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, NH, N(C₁₋₄ alkyl), O, and S(O)_(p);

ring B is independently a benzene ring or a 5- to 6-membered heteroarylcomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p);

ring C is independently a benzene ring or a 5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, NH, N(C₁₋₄ alkyl), O, and S(O)_(p);

L₁ is independently selected from the group consisting of: a bond,—CHR⁵—, —CHR⁵CHR⁵—, —CR⁵═CR⁵—, —C≡C—, —OCH₂—, —CHR⁵NH—, —CH₂O—, —SCH₂—,—SO₂CH₂—, —CH₂NH—, and —CR⁵R⁵—;

L is independently selected from the group consisting of: C₃₋₈ alkylene,C₃₋₈ alkenylene, and C₄₋₈ alkynylene; wherein said alkylene, alkenyleneand alkynylene are substituted with 0-2 R⁷ and optionally one or more ofthe carbon atoms of said alkylene and alkenylene may be replaced by O,S, NH, N(C₁₋₄ alkyl), CO, CONH, NHCO, OCONH, NHCO₂, —NHCONH—, SO₂NH,NHSO₂, CON(C₁₋₄ alkyl), or N(C₁₋₄ alkyl)CO;

Y is independently selected from the group consisting of: CH₂, CH(C₁₋₄alkyl), C(C₁₋₄ alkyl)₂, CO, O, S, NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)),—N(C₁₋₄ alkyl)CH₂—, —N(CO₂(C₁₋₄ alkyl))CH₂—, —N(CH₂CO₂(C₁₋₄ alkyl))CH₂—,—CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —OCON(C₁₋₄alkyl)-, —NHCONH—, —SO₂NH—, —NHCO₂—, and —NHSO₂—;

alternatively, L-Y is —C₃₋₆ alkylene-CH═N—;

R¹ is, independently at each occurrence, selected from the groupconsisting of halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄haloalkyl, OH, OCH₂F, OCHF₂, OCF₃, CN, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄alkyl)₂, CO₂(C₁₋₄ alkyl), CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —C(═NH)NH₂, and phenyl substituted with 0-2 R^(a);

R² is independently a 5- to 7-membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p), wherein said heterocycle is substituted with 0-2 R^(2a);

R^(2a) is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, —CH₂OH, C₁₋₄ alkoxy, OH, CF₃, OCF₃,CN, NH₂, CO₂H, CO₂(C₁₋₄ alkyl), COC₁₋₄ alkyl, —CONH₂, —CONH(C₁₋₄ alkyl),—CON(C₁₋₄ alkyl)₂, —SO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), and—SO₂N(C₁₋₄ alkyl)₂;

R³ is independently selected from the group consisting of H, ═O,halogen, OH, NH₂, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, —CH₂OH,CO₂H, CO₂(C₁₋₄ alkyl), —C(O)NH₂, —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄alkyl)₂, —CH₂CO₂H, and C₃₋₆ cycloalkyl;

R⁴ is independently selected from the group consisting of H, and C₁₋₄alkyl;

R⁵ is, independently at each occurrence, selected from the groupconsisting of H, halogen, OH, and C₁₋₄ alkyl;

R⁶ is, independently at each occurrence, selected from the groupconsisting of halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂,—CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl),—NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂CH₂CH(C₁₋₄alkyl)O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂, —CONH(C₁₋₄ alkyl),—CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, and —NHCO₂(CH₂)₀₋₂R⁹;

R⁷ is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, NH₂, CH₂NH₂, C₁₋₄ haloalkyl, OCH₂F, OCHF₂,OCF₃, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄alkyl), CH₂O(CH₂)₀₋₄O(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl),CO₂(CH₂)₂O(C₁₋₄ alkyl), CO₂(C₁₋₄ haloalkyl), CO₂(CH₂)₂SO₂(C₁₋₄ alkyl),CH₂CO₂H, CH₂CO₂(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂,—OCO(C₁₋₄ alkyl), —CH₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH(C₁₋₄ alkoxy),—CO₂(CH₂)₂O(C₁₋₄ alkyl), —CO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —CONH(CH₂)₂O(C₁₋₄alkyl), —CONH(CH₂)₂N(C₁₋₄ alkyl)₂, —CON(C₁₋₄ alkyl)(CH₂)₂O(C₁₋₄ alkyl),—CON(C₁₋₄ alkyl)(CH₂)₂N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl, —CONHBn, —CONH(OBn),—(CO)₀₋₁(CH₂)₀₋₃—C₃₋₆ carbocycle, and—(CH₂)₀₋₁—(CO)₀₋₁—(W)₀₋₁—(CH₂)₀₋₂-(4- to 6-membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C₁₋₄alkyl), O, and S(O)_(p)); wherein said carbocycle and heterocycle aresubstituted with 0-2 R⁸;

R⁸ is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, CHF₂, CF₃, C₁₋₄ alkoxy, CH₂OH, CO₂H,CO₂(C₁₋₄ alkyl), CONH₂, and C₁₋₄ alkyl;

R⁹ is a 4- to 6-membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)), O,and S(O)_(p);

R^(a) is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, CF₃, C₁₋₄ alkoxy, and C₁₋₄ alkyl;

W is independently selected from the group consisting of: O, NH andN(C₁₋₄ alkyl); and

p is, independently at each occurrence, selected from the groupconsisting of: 0, 1, and 2.

In a second aspect, the present invention provides compounds of Formula(I), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,a solvate, or a prodrug thereof, within the scope of the first aspect,wherein:

ring A is independently a 6-membered carbocycle, a 9- to 10-memberedcarbocycle, or a 5- to 10-membered heterocycle comprising: carbon atomsand 1-3 heteroatoms selected from N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p);

ring B is independently selected from the group consisting of:imidazole, oxazole, oxadiazole, triazole, pyridine, pyridazine,pyrimidine, and benzene; and

ring C is independently selected from the group consisting of: benzene,pyridine, indazole, indole, benzimidazole, quinoline, isoquinoline,tetrahydroquinoline, tetrahydroisoquinoline, and quinazoline.

In a third aspect, the present invention provides compounds of Formula(I), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,a solvate, or a prodrug thereof, within the scope of the first or secondaspect, wherein:

ring A is independently selected from the group consisting of: benzene,cyclohexane, indane, tetrahydronaphthalene, naphthalene, isoxazoline,isoxazole, pyrazole, imidazole, triazole, piperidine, pyridine,indazole, indole, benzimidazole, quinoline, isoquinoline,tetrahydroquinoline, and tetrahydroisoquinoline;

is independently selected from the group consisting of:

is independently selected from the group consisting of:

In a fourth aspect, the present invention provides compounds of Formula(II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, wherein:

is independently selected from the group consisting of:

L₁ is independently selected from the group consisting of: a bond,—CHR⁵CHR⁵—, —CR⁵═CHR⁵—, —C≡C—, —OCH₂—, —CHR⁵NH—, —CH₂O—, —SCH₂—,—SO₂CH₂—, —CH₂NH—, and —CR⁵R⁵—;

L is independently selected from the group consisting of: C₃₋₈ alkyleneand C₃₋₈ alkenylene; wherein said alkylene and alkenylene aresubstituted with 0-2 R⁷ and optionally one or two of the carbon atoms ofsaid alkylene and alkenylene may be replaced by O, CO, S, NH, N(C₁₋₄alkyl), CONH—, NHCO, OCONH, SO₂NH, or CON(C₁₋₄ alkyl);

Y is independently selected from the group consisting of: CH₂, CO,CH(C₁₋₄ alkyl), C(C₁₋₄ alkyl)₂, O, S, NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄alkyl), —N(C₁₋₄ alkyl)CH₂—, —N(CO₂(C₁₋₄ alkyl))CH₂—, —N(CH₂CO₂(C₁₋₄alkyl))CH₂—, —CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—,—OCON(C₁₋₄ alkyl)-, —NHCONH—, and —SO₂NH—;

alternatively, L-Y is —C₃₋₆ alkylene-CH═N—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄haloalkyl, OH, OCH₂F, OCHF₂, OCF₃, CN, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄alkyl)₂, CO₂(C₁₋₄ alkyl), CO(C₁₋₄ alkyl), —OCH₂CO₂H, —CH₂NH₂, —CONH₂,—CONH(C₁₋₄ alkyl), —SO₂NH₂, and —C(═NH)NH₂;

R² is independently a 5- to 6-membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NH, O, and S(O)_(p), whereinsaid heterocycle is substituted with 0-2 R^(2a);

R^(2a) is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, —CH₂OH, C₁₋₄ alkoxy, OH, CF₃, CN,NH₂, CO₂H, CO₂(C₁₋₄ alkyl), COC₁₋₄ alkyl, —CONH₂, —CONH(C₁₋₄ alkyl), and—CON(C₁₋₄ alkyl)₂;

R³ is independently selected from the group consisting of: H, halogen,OH, NH₂, CN, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, —CH₂OH, CO₂H, CO₂(C₁₋₄alkyl), C(O)NH₂, —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, —CH₂CO₂H, andC₃₋₆ cycloalkyl;

R⁴ is independently selected from the group consisting of: H and C₁₋₄alkyl;

R⁵ is, independently at each occurrence, selected from the groupconsisting of: H, halogen, OH, and C₁₋₄ alkyl;

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂,—CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl),—NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl),—SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH(CH₂)₂O(C₁₋₄ alkyl),CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCOCF₃, and —NHCO₂(CH₂)₀₋₁R⁹;

R⁷ is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, CH₂OH,CH₂O(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), CO₂(CH₂)₂O(C₁₋₄ alkyl)),CO₂CH₂CF₃, CO₂(CH₂)₂SO₂(C₁₋₄ alkyl, CH₂CO₂H, CH₂CO₂(C₁₋₄ alkyl), CONH₂,CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, —OCO(C₁₋₄ alkyl), —CH₂NH(CH₂)₂O(C₁₋₄alkyl), —CO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —CONH(CH₂)₂O(C₁₋₄ alkyl),—CONH(CH₂)₂N(C₁₋₄ alkyl)₂, —CON(C₁₋₄ alkyl)(CH₂)₂O(C₁₋₄ alkyl),—CONH(CH₂)₂N(C₁₋₄ alkyl)₂, —CON(C₁₋₄ alkyl)(CH₂)₂N(C₁₋₄ alkyl)₂,—CONH(C₁₋₄ alkoxy), —CONHBn, —CONH(OBn), —(CH₂)₁₋₃Ph, C₁₋₄ alkyl, and—(CH₂)₀₋₁—(CO)₀₋₁—(W)₀₋₁—(CH₂)₀₋₂-(4- to 6-membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C₁₋₄alkyl), O, and S(O)_(p)); wherein said heterocycle is substituted with0-2 R⁸;

R⁸ is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, CHF₂, CF₃, C₁₋₄ alkoxy, and C₁₋₄ alkyl;

R⁹ is a 4- to 6-membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)), O,and S(O)_(p);

W is independently selected from the group consisting of: O and NH; and

p is, independently at each occurrence, selected from the groupconsisting of: 0, 1, and 2.

In a fifth aspect, the present invention provides compounds of Formula(IIa) or Formula (IIb):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, within the scope of the fourth aspect.

In a sixth aspect, the present invention provides compounds of Formula(IIc) or Formula (IId):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, within the scope of the fourth aspect.

In a seventh aspect, the present invention provides compounds of Formula(IIe) or Formula (IIf):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, within the scope of the fourth aspect.

In an eighth aspect, the present invention includes compounds of Formula(I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) a stereoisomer, atautomer, a pharmaceutically acceptable salt, a solvate, or a prodrugthereof, within the scope of any of the above aspects, wherein:

L₁ is independently selected from the group consisting of: a bond,—CH₂CH₂—, —CH═CH—, —C(Me)=CH—, —C≡C—, and —CH₂NH— in Formula (I), (II),(IIa), (IIb), (IIe) or (IIf);

L is independently selected from the group consisting of: C₃₋₇ alkyleneand C₃₋₇ alkenylene; wherein said alkylene and alkenylene aresubstituted with 0-2 R⁷ and optionally one or two of the carbon atoms ofsaid alkylene and alkenylene may be replaced by O, CO, NH, N(C₁₋₄alkyl), CONH, NHCO, or CON(C₁₋₄ alkyl);

Y is independently selected from the group consisting of: CH₂, CO,CH(C₁₋₄ alkyl), C(C₁₋₄ alkyl)₂, O, S, NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄alkyl)), —N(C₁₋₄ alkyl)CH₂—, —N(CO₂(C₁₋₄ alkyl))CH₂—, —N(CH₂CO₂(C₁₋₄alkyl))CH₂—, —CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—,—NHCONH—, and —SO₂NH—;

alternatively, L-Y is —(CH₂)₃₋₆—CH═N—;

R¹ is, independently at each occurrence, selected from: halogen, CN, OH,OCH₂F, OCHF₂, OCF₃, C₁₋₄ haloalkyl, C₁₋₄ alkyl, C₁₋₄ alkoxy, CO(C₁₋₄alkyl), NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, —C(═NH)NH₂, —C(O)NH₂,—CH₂NH₂, and —SO₂NH₂;

R³ is independently selected from the group consisting of: H, halogen,OH, NH₂, CN, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, —CH₂OH, CO₂H, CO₂(C₁₋₄alkyl), C(O)NH₂, —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, —CH₂CO₂H, andC₃₋₆ cycloalkyl; and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂,—CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl),—NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl),—SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl),CON(C₁₋₄ alkyl)₂, —NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCOCF₃, and—NHCO₂(CH₂)₀₋₁R⁹.

In a ninth aspect, the present invention includes compounds of Formula(I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or a stereoisomer,a tautomer, a pharmaceutically acceptable salt, a solvate, or a prodrugthereof, within the scope of any of the above aspects, wherein:

L₁ is independently selected from the group consisting of: a bond,—CH₂CH₂— and —CH═CH— in Formula (I), (II), (IIa), (IIb), (IIe) or (IIf);

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, CN, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, CH₂F, CHF₂,CF₃, OCH₂F, OCHF₂, OCF₃, CO(C₁₋₄ alkyl), NH₂, NH(C₁₋₄ alkyl)₂, N(C₁₋₄alkyl)₂, —CH₂NH₂, and —C(═NH)NH₂;

R³ is independently selected from the group consisting of: H, halogen,CN, CF₃, CO₂H, CO₂(C₁₋₄ alkyl), C₁₋₄ alkyl, CONH₂, CON(C₁₋₄ alkyl)₂, andC₃₋₆ cycloalkyl; and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄ alkyl),—NHCO₂(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄ alkyl), —CONH₂, CONH(C₁₋₄ alkyl),CON(C₁₋₄ alkyl)₂, —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂CH₂CO₂H, —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCOCF₃,

In a tenth aspect, the present invention includes compounds of Formula(I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or a stereoisomer,a tautomer, a pharmaceutically acceptable salt, a solvate, or a prodrugthereof, within the scope of any one of the above aspects, wherein:

L₁ is independently selected from the group consisting of: a bond and—CH═CH— in Formula (I), (II), (IIa), (IIb), (IIe) or (IIf);

L is independently selected from the group consisting of: —(CH₂)₃₋₆—,—(CH₂)₂₋₄CH(C₁₋₄ alkyl)(CH₂)₀₋₂—, —(CH₂)₁₋₂—CH═CH—(CH₂)₀₋₃—,—CH₂—CH═C(C₁₋₄ alkyl)-(CH₂)₁₋₂—, —CH₂—C(C₁₋₄ alkyl)═CH—(CH₂)₁₋₂—,—CH₂—CH═CH—CH₂CH(C₁₋₄ alkyl)-, —CH₂—CH═CH—CH(C₁₋₄ alkyl)-(CH₂)₀₋₂—,—CH₂—CH═CH—CH₂C(halo)₂-, —CH₂—CH═CH—(CH₂)₁₋₂CH(CF₃)—,—CH₂—CH═CH—CH(OH)CH₂—, —(CH₂)₃CH(halo)-, —(CH₂)₃₋₄C(halo)₂-,—(CH₂)₄CH(CH₂OH)—, —(CH₂)₃₋₄CH(C₁₋₄ alkoxy)-, —(CH₂)₄CH(CH₂(C₁₋₄alkoxy))-, —(CH₂)₄CH(CO₂H)—, —(CH₂)₄CH(CH₂CO₂H)—, —(CH₂)₄₋₅CH(CO₂(C₁₋₄alkyl))-, —(CH₂)₄CH(CH₂CO₂(C₁₋₄ alkyl))-, —(CH₂)₄CH(CO₂CH₂CF₃)—,—(CH₂)₄CH(CO₂(CH₂)₂SO₂(C₁₋₄ alkyl))-, —(CH₂)₄C(C₁₋₄ alkyl)(CO₂(C₁₋₄alkyl))-, —(CH₂)₄C(CF₃)(CO₂(C₁₋₄ alkyl))-, —(CH₂)₄CH(CONH₂))—,—(CH₂)₄CH(CONH(C₁₋₄ alkyl))-, —(CH₂)₄CH(CON(C₁₋₄ alkyl)₂)—,—(CH₂)₃CH(C₁₋₄ alkyl)CH(CONH₂)—, —(CH₂)₄CH(CO₂(CH₂)₂O(C₁₋₄ alkyl))-,—(CH₂)₄CH(CH₂NH(CH₂)₂O(C₁₋₄ alkyl))-, —(CH₂)₄CH(CONH(C₁₋₄ alkoxy))-,—(CH₂)₄CH(CONH(OBn))-, —(CH₂)₄CH((CH₂)₃Ph)-, —(CH₂)₄CH(CO₂(CH₂)₂N(C₁₋₄alkyl)₂)-, —(CH₂)₄CH(CONH(CH₂)₂O(C₁₋₄ alkyl))-,—(CH₂)₄CH(CONH(CH₂)₂N(C₁₋₄ alkyl)₂)-, —(CH₂)₄CH(CON(C₁₋₄alkyl)(CH₂)₂O(C₁₋₄ alkyl))-, —(CH₂)₄CH(CON(C₁₋₄ alkyl)(CH₂)₂N(C₁₋₄alkyl)₂)-, —(CH₂)₄CH(CH(halo)₂)-, —(CH₂)₄₋₅CH(CF₃)—,—(CH₂)₃C(halo)₂CH₂—, —(CH₂)—CH(OH)(CH₂)₁₋₂—, —CH₂CH(OH)CH(OH)CH₂—,—(CH₂)₃CH(OCO(C₁₋₄ alkyl))CH₂—, —(CH₂)₃C(O)CH₂—, —CH₂O(CH₂)₂₋₄—,—CH₂NH(CH₂)₂₋₄—, (CH₂)₂₋₃NH(CH₂)₁₋₂—, —(CH₂)₂₋₄N(C₁₋₄ alkyl)(CH₂)₀₋₂—,—CH₂CONH(CH₂)₂₋₄—, —CH₂CON(C₁₋₄ alkyl)(CH₂)₂₋₄—, —CH₂NHCOC(halo)₂CH₂—,—(CH₂)₄CH(3-C₁₋₄ alkyl-oxetan-3-yl)-, —(CH₂)₄CH(thiazol-4-yl)-,—(CH₂)₄CH(4-C₁₋₄ alkyl-thiazol-2-yl)-, —(CH₂)₄CH(1-C₁₋₄alkyl-imidazol-2-yl)-, —(CH₂)₄CH(1-C₁₋₄ alkyl-pyrazol-3-yl)-,—(CH₂)₄CH(1-C₁₋₄ alkyl-pyrazol-5-yl)-, —CH₂—CH═CH—CH₂CH(1-C₁₋₄alkyl-pyrazol-5-yl)-, —(CH₂)₄CH(1-C₁₋₄ alkyl-3-C₁₋₄alkyl-pyrazol-5-yl)-, —(CH₂)₄CH(1-C₁₋₄ alkyl-4-halo-pyrazol-3-yl)-,

Y is independently selected from the group consisting of: CH₂, CO, O,NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)), —N(C₁₋₄ alkyl)CH₂—, —N(CO₂(C₁₋₄alkyl))CH₂—, —N(CH₂CO₂(C₁₋₄ alkyl))CH₂—, —CONH—, —NHCO—, —CONHCH₂—,—CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —NHCONH—, and —SO₂NH—; and

alternatively, L-Y is —(CH₂)₃₋₆—CH═N—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), CN,CH₂F, CHF₂, CF₃, OCHF₂, NH₂, N(C₁₋₄ alkyl)₂, —CH₂NH₂, and —C(═NH)NH₂;

R³ is independently selected from the group consisting of: H, halogen,C₁₋₄ alkyl, CN, CO₂(C₁₋₄ alkyl), CONH₂, CON(C₁₋₄ alkyl)₂, and C₃₋₆cycloalkyl; and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, NH₂, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄alkyl), CON(C₁₋₄ alkyl)₂, —NHCO₂(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄ alkyl),—NHCO₂CH₂CO₂H, —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂,—NHCOCF₃,

In an 11th aspect, the present invention includes compounds of Formula(III) or Formula (IIIa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, wherein:

L₁ is independently selected from the group consisting of: a bond and—CH═CH— in Formula (IIIa);

L is independently selected from the group consisting of: —(CH₂)₃—,—(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₃CH(C₁₋₄ alkyl)-, —(CH₂)₄CH(C₁₋₄alkyl)-, —(CH₂)₂CH(C₁₋₄ alkyl)CH₂—, —(CH₂)₃CH(C₁₋₄ alkyl)CH₂—,—(CH₂)₂CH(C₁₋₄ alkyl)(CH₂)₂—, —(CH₂)₃CH(C₁₋₄ alkyl)(CH₂)₂—,—(CH₂)₄CH(C₁₋₄ alkyl)CH₂—, —(CH₂)₄CH(C₁₋₄ alkyl)(CH₂)₂—, —(CH₂)₂—CH═CH—,—CH₂—CH═CH—CH₂—, —CH₂—CH═CH—(CH₂)₂—, —CH₂—CH═CH—(CH₂)₃—, —CH₂—CH═C(C₁₋₄alkyl)-(CH₂)₂—, —CH₂—CH═CH—CH₂CH(C₁₋₄ alkyl)-, —CH₂—CH═CH—CH(C₁₋₄alkyl)CH₂—, —CH₂—CH═CH—CH₂C(halo)₂-, —CH₂—CH═CH—CH₂CH(CF₃)—,—CH₂—CH═CH—(CH₂)₂CH(CF₃)—, —CH₂—CH═CH—CH(OH)CH₂—, —(CH₂)₃CH(halo)-,—(CH₂)₃C(halo)₂-, —(CH₂)₄C(halo)₂-, —(CH₂)₄CH(CH₂OH)—, —(CH₂)₃CH(C₁₋₄alkoxy)-, —(CH₂)₄CH(CH₂(C₁₋₄ alkoxy))-, —(CH₂)₄CH(CO₂H)—,—(CH₂)₄CH(CH₂CO₂H)—, —(CH₂)₄CH(CO₂(C₁₋₄ alkyl))-, —(CH₂)₄CH(CH₂CO₂(C₁₋₄alkyl))-, —(CH₂)₄CH(CO₂CH₂CF₃)—, —(CH₂)₄CH(CO₂(CH₂)₂SO₂(C₁₋₄ alkyl))-,—(CH₂)₅CH(CO₂(C₁₋₄ alkyl))-, —(CH₂)₄C(C₁₋₄ alkyl)(CO₂(C₁₋₄ alkyl))-,—(CH₂)₄C(CF₃)(CO₂(C₁₋₄ alkyl))-, —(CH₂)₄CH(CONH₂)—, —(CH₂)₄CH(CONH(C₁₋₄alkyl))-, —(CH₂)₄CH(CON(C₁₋₄ alkyl)₂)-, —(CH₂)₃CH(C₁₋₄ alkyl)CH(CONH₂)—,—(CH₂)₄CH(CONH(C₁₋₄ alkoxy))-, —(CH₂)₄CH(CONH(OBn))-,—(CH₂)₄CH((CH₂)₃Ph)-, —(CH₂)₄CH(CON(C₁₋₄ alkyl)(CH₂)₂O(C₁₋₄ alkyl))-,—(CH₂)₄CH(CON(C₁₋₄ alkyl)(CH₂)₂N(C₁₋₄ alkyl)₂)-, —(CH₂)₄CH(CH(halo)₂)-,—(CH₂)₄CH(CF₃)—, —(CH₂)₅CH(CF₃)—, —(CH₂)₃C(halo)₂CH₂—,—CH₂CH(OH)(CH₂)₂—, —(CH₂)₂CH(OH)CH₂—, —(CH₂)₃CH(OH)CH₂—,—CH₂CH(OH)CH(OH)CH₂—, —(CH₂)₃CH(OCO(C₁₋₄ alkyl))CH₂—, —(CH₂)₃C(O)CH₂—,—CH₂O(CH₂)₃—, —CH₂O(CH₂)₄—, —CH₂NH(CH₂)₂—, —CH₂NH(CH₂)₃—, —CH₂NH(CH₂)₄—,—(CH₂)₂N(C₁₋₄ alkyl)CH₂—, —(CH₂)₂N(C₁₋₄ alkyl)(CH₂)₂—, —CH₂CONH(CH₂)₂—,—CH₂CONH(CH₂)₃—, —CH₂CONH(CH₂)₄—, —CH₂CON(C₁₋₄ alkyl)(CH₂)₂—,—CH₂CON(C₁₋₄ alkyl)(CH₂)₃—, —(CH₂)₄CH(thiazol-4-yl)-, —(CH₂)₄CH(4-C₁₋₄alkyl-thiazol-2-yl)-, —(CH₂)₄CH(1-C₁₋₄ alkyl-imidazol-2-yl)-,—(CH₂)₄CH(1-C₁₋₄ alkyl-pyrazol-3-yl)-, —(CH₂)₄CH(1-C₁₋₄alkyl-pyrazol-5-yl)-, —CH₂—CH═CH—CH₂CH(1-C₁₋₄ alkyl-pyrazol-5-yl)-,—(CH₂)₄CH(1-C₁₋₄ alkyl-3-C₁₋₄ alkyl-pyrazol-5-yl)-, —(CH₂)₄CH(1-C₁₋₄alkyl-4-halo-pyrazol-3-yl)-,

Y is independently selected from the group consisting of: CH₂, CO, O,NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)), —N(C₁₋₄ alkyl)CH₂—, —N(CO₂(C₁₋₄alkyl))CH₂—, —N(CH₂CO₂(C₁₋₄ alkyl))CH₂—, —CONH—, —NHCO—, —CONHCH₂—,—CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —NHCONH—, and —SO₂NH—;

alternatively, L-Y is —(CH₂)₄—CH═N—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), CN,CH₂F, CHF₂, CF₃, OCHF₂, NH₂, N(C₁₋₄ alkyl)₂, —CH₂NH₂, and —C(═NH)NH₂ inFormula (IIIa);

R^(1b) is independently selected from the group consisting of: H andhalogen in Formula (III);

R² is independently a 5-membered heterocycle selected from: triazolyland tetrazolyl in Formula (IIIa);

R³ is independently selected from the group consisting of: H, halogen,C₁₋₄ alkyl, CN, CO₂(C₁₋₄ alkyl), CONH₂, CON(C₁₋₄ alkyl)₂, and C₃₋₆cycloalkyl; and

R⁶ is independently selected from the group consisting of: halogen, NH₂,CO₂H, CONH₂, CO₂(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH,—NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂CH₂CO₂H, —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄alkyl), —NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCOCF₃,

In a 12th aspect, the present invention includes compounds of Formula(III) or Formula (IIIa), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,within the scope of the 11^(th) aspect, wherein:

L is independently selected from the group consisting of: —(CH₂)₄—,—(CH₂)₅—, —(CH₂)₆—, —(CH₂)₃CH(C₁₋₄ alkyl)-, —(CH₂)₄CH(C₁₋₄ alkyl)-,—(CH₂)₂CH(C₁₋₄ alkyl)CH₂, —(CH₂)₃CH(C₁₋₄ alkyl)CH₂—, —(CH₂)₂CH(C₁₋₄alkyl)(CH₂)₂—, —(CH₂)₃CH(C₁₋₄ alkyl)(CH₂)₂—, —(CH₂)₄CH(C₁₋₄ alkyl)CH₂—,—(CH₂)₄CH(C₁₋₄ alkyl)(CH₂)₂—, —(CH₂)₂—CH═CH—, —CH₂—CH═CH—CH₂—,—CH₂—CH═CH—(CH₂)₂—, —CH₂—CH═CH—(CH₂)₃—, —CH₂—CH═C(C₁₋₄ alkyl)-(CH₂)₂—,—CH₂—CH═CH—CH₂CH(C₁₋₄ alkyl)-, —CH₂—CH═CH—CH(C₁₋₄ alkyl)CH₂—,—CH₂—CH═CH—CH₂C(halo)₂-, —CH₂—CH═CH—CH₂CH(CF₃)—,—CH₂—CH═CH—(CH₂)₂CH(CF₃)—, —CH₂—CH═CH—CH(OH)CH₂—, —(CH₂)₃CH(halo)-,—(CH₂)₃C(halo)₂-, —(CH₂)₄C(halo)₂-, —(CH₂)₄CH(CH₂OH)—,—(CH₂)₄CH(CH₂(C₁₋₄ alkoxy))-, —(CH₂)₃CH(C₁₋₄ alkoxy)-, —(CH₂)₄CH(C₁₋₄alkoxy)-, —(CH₂)₄CH(CO₂H)—, —(CH₂)₄CH(CH₂CO₂H)—, —(CH₂)₄CH(CO₂(C₁₋₄alkyl))-, —(CH₂)₄CH(CH₂CO₂(C₁₋₄ alkyl))-, —(CH₂)₄CH(CO₂CH₂CF₃)—,—(CH₂)₄CH(CO₂(CH₂)₂SO₂(C₁₋₄ alkyl))-, —(CH₂)₅CH(CO₂(C₁₋₄ alkyl))-,—(CH₂)₄C(C₁₋₄ alkyl)(CO₂(C₁₋₄ alkyl))-, —(CH₂)₄C(CF₃)(CO₂(C₁₋₄ alkyl))-,—(CH₂)₄CH(CONH₂)—, —(CH₂)₄CH(CONH(C₁₋₄ alkyl))-, —(CH₂)₄CH(CON(C₁₋₄alkyl)₂)-, —(CH₂)₃CH(C₁₋₄ alkyl)CH(CONH₂)—, —(CH₂)₄CH(CONH(C₁₋₄alkoxy))-, —(CH₂)₄CH(CONH(OBn))-, —(CH₂)₄CH(CON(C₁₋₄ alkyl)(CH₂)₂O(C₁₋₄alkyl))-, —(CH₂)₄CH(CON(C₁₋₄ alkyl)(CH₂)₂N(C₁₋₄ alkyl)₂)-,—(CH₂)₄CH(CH(halo)₂)-, —(CH₂)₄CH(CF₃)—, —(CH₂)₅CH(CF₃)—,—(CH₂)₃C(halo)₂CH₂—, —CH₂CH(OH)(CH₂)₂—, —(CH₂)₂CH(OH)CH₂—,—(CH₂)₃CH(OH)CH₂—, —CH₂CH(OH)CH(OH)CH₂—, —(CH₂)₃CH(OCO(C₁₋₄ alkyl))CH₂—,—(CH₂)₃C(O)CH₂—, —CH₂O(CH₂)₃—, —CH₂O(CH₂)₄—, —CH₂NH(CH₂)₂—,—CH₂NH(CH₂)₃—, —CH₂NH(CH₂)₄—, —(CH₂)₂N(C₁₋₄ alkyl)CH₂—, —(CH₂)₂N(C₁₋₄alkyl)(CH₂)₂—, —CH₂CONH(CH₂)₂—, —CH₂CONH(CH₂)₃—, —CH₂CONH(CH₂)₄—,—CH₂CON(C₁₋₄ alkyl)(CH₂)₂—, —CH₂CON(C₁₋₄ alkyl)(CH₂)₃—,—(CH₂)₄CH(thiazol-4-yl)-, —(CH₂)₄CH(4-C₁₋₄ alkyl-thiazol-2-yl)-,—(CH₂)₄CH(1-C₁₋₄ alkyl-imidazol-2-yl)-, —(CH₂)₄CH(1-C₁₋₄alkyl-pyrazol-3-yl)-, —(CH₂)₄CH(1-C₁₋₄ alkyl-pyrazol-5-yl)-,—CH₂—CH═CH—CH₂CH(1-C₁₋₄ alkyl-pyrazol-5-yl)-, —(CH₂)₄CH(1-C₁₋₄alkyl-3-C₁₋₄ alkyl-pyrazol-5-yl)-, —(CH₂)₄CH(1-C₁₋₄alkyl-4-halo-pyrazol-3-yl)-,

Y is independently selected from the group consisting of: CH₂, O, NH,—CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —N(C₁₋₄ alkyl)CH₂—,—N(CO₂(C₁₋₄ alkyl))CH₂—, —N(CH₂CO₂(C₁₋₄ alkyl))CH₂—, —OCONH—, —NHCONH—,and —SO₂NH—;

alternatively, L-Y is —(CH₂)₄—CH═N—; and

R⁶ is independently selected from the group consisting of: halogen, NH₂,CO₂H, CONH₂, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), —NHCO₂CH₂CO₂H,

In a 13th aspect, the present invention includes compounds of Formula(III), or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, a solvate, or a prodrug thereof, wherein:

L-Y is independently selected from the group consisting of: —(CH₂)₆—,—(CH₂)₇—, —(CH₂)₄CH(CO₂H)CH₂—, —(CH₂)₄CH(CO₂(C₁₋₄ alkyl))CH₂—,—(CH₂)₄CH(CONH₂)CH₂—, —(CH₂)₄CH(CONH(C₁₋₄ alkyl))CH₂—,—(CH₂)₄CH(CON(C₁₋₄ alkyl)₂)CH₂—, —(CH₂)₄CF₂CO—, —CH₂—CH═CH—(CH₂)₃—,—CH₂—CH═CH—(CH₂)₄—, —CH₂CON(C₁₋₄ alkyl)(CH₂)₃—, —CH₂CON(C₁₋₄alkyl)(CH₂)₄—, —(CH₂)₄N(C₁₋₄ alkyl)CH₂—, —(CH₂)₄N(CO₂(C₁₋₄ alkyl))CH₂—,—(CH₂)₄N(CH₂CO₂(C₁₋₄ alkyl))CH₂—, —(CH₂)₅O—, —(CH₂)₆O—, —(CH₂)₃CH(C₁₋₄alkyl)(CH₂)₂O—, —(CH₂)₄CH(C₁₋₄ alkyl)CH₂O—, —CH₂CONH(CH₂)₂O—,—CH₂NH(CH₂)₄O—, —CH₂—CH═CH—(CH₂)₂O—, —CH₂—CH═CH—(CH₂)₃O—, —(CH₂)₅NH—,—(CH₂)₆NH—, —(CH₂)₃CH(C₁₋₄ alkyl)CH₂NH—, —(CH₂)₄CH(C₁₋₄ alkyl)NH—,—(CH₂)₄CH(C₁₋₄ alkyl)CH₂NH—, —(CH₂)₄CH(CH₂OH)NH—,—(CH₂)₄CH(CH₂(C₁₋₄alkoxy))NH—, —(CH₂)₄CH(CO₂H)NH—,—(CH₂)₄CH((CH₂)₃Ph)NH—, —(CH₂)₄CH(CH₂CO₂H)NH—, —(CH₂)₄CH(CH₂CO₂(C₁₋₄alkyl))NH—, —(CH₂)₄CH(CO₂(C₁₋₄ alkyl))NH—, —(CH₂)₄CH(CO₂CH₂CF₃)NH—,—(CH₂)₄CH(CO₂(CH₂)₂SO₂(C₁₋₄ alkyl))NH—, —(CH₂)₅CH(CO₂(C₁₋₄ alkyl))NH—,—(CH₂)₄CH(CONH₂)NH—, —(CH₂)₄CH(CONH(C₁₋₄ alkyl))NH—, —(CH₂)₄CH(CON(C₁₋₄alkyl)₂)NH—, —(CH₂)₄C(C₁₋₄ alkyl)(CO₂(C₁₋₄ alkyl))NH—,—(CH₂)₄C(CF₃)(CO₂(C₁₋₄ alkyl))NH—, —(CH₂)₃CH(C₁₋₄ alkyl)CH(CONH₂)NH—,—(CH₂)₄CH(CONH(C₁₋₄ alkoxy))NH—, —(CH₂)₄CH(CONH(OBn))NH—,—(CH₂)₄CH(CON(C₁₋₄ alkyl)(CH₂)₂O(C₁₋₄ alkyl))NH—, —(CH₂)₄CH(CON(C₁₋₄alkyl)(CH₂)₂N(C₁₋₄ alkyl)₂)NH—, —CH₂—CH═CH—(CH₂)₂NH—,—CH₂—CH═CH—(CH₂)₃NH—, —(CH₂)₄CH(CHF₂)NH—, —(CH₂)₄CH(CF₃)NH—,—(CH₂)₅CH(CF₃)NH—, —(CH₂)₃CF₂CH₂NH—, —CH₂—CH═CH—CH₂CH(CF₃)NH—,—CH₂—CH═CH—(CH₂)₂CH(CF₃)NH—, —CH₂CONH(CH₂)₂NH—, —CH₂CONH(CH₂)₃NH—,—CH₂NHCOCF₂CH₂NH—, —CH₂CONH(CH₂)₄NH—, —(CH₂)₄CH(CO-pyrrolidin-1-yl)NH—,—(CH₂)₄CH(thiazol-4-yl)NH—, —(CH₂)₄CH(4-C₁₋₄ alkyl-thiazol-2-yl)NH—,—(CH₂)₄CH(1-C₁₋₄ alkyl-imidazol-2-yl)NH—, —(CH₂)₄CH(1-C₁₋₄alkyl-pyrazol-3-yl)NH—, —(CH₂)₄CH(1-C₁₋₄ alkyl-pyrazol-5-yl)NH—,—(CH₂)₄CH(1-C₁₋₄ alkyl-3-C₁₋₄ alkyl-pyrazol-5-yl)NH—, —(CH₂)₄CH(1-C₁₋₄alkyl-4-halo-pyrazol-3-yl)NH—, —CH₂—CH═CH—CH₂CH(1-C₁₋₄alkyl-pyrazol-5-yl)NH—, —(CH₂)₆N(C₁₋₄ alkyl)-, —(CH₂)₅N(CO₂(C₁₋₄alkyl))-, —(CH₂)₄CONH—, —(CH₂)₅CONH—, —(CH₂)₆CONH—, —(CH₂)₃CH(C₁₋₄alkyl)CONH—, —(CH₂)₄CH(C₁₋₄ alkyl)CONH—, —(CH₂)₂CH(C₁₋₄ alkyl)CH₂CONH—,—(CH₂)₃CH(C₁₋₄ alkyl)CH₂CONH—, —(CH₂)₂CH(C₁₋₄ alkyl)(CH₂)₂CONH—,—(CH₂)₂—CH═CH—CONH—, —CH₂—CH═CH—CH₂CONH—, —CH₂—CH═CH—(CH₂)₂CONH—,—CH₂—CH═CH—(CH₂)₃CONH—, —CH₂—CH═CH—CH₂CH(C₁₋₄ alkyl)CONH—,—CH₂—CH═CH—CH(C₁₋₄ alkyl)CH₂CONH—, —CH₂—CH═C(C₁₋₄ alkyl)(CH₂)₂CONH—,—(CH₂)₃CH(C₁₋₄ alkyl)CONH—, —(CH₂)₃CHFCONH—, —(CH₂)₃CF₂CONH—,—(CH₂)₄CF₂CONH—, —CH₂—CH═CH—CH₂CF₂CONH—, —(CH₂)₃CH(CF₃)CONH—,—CH₂CH(OH)(CH₂)₂CONH—, —(CH₂)₂CH(OH)CH₂CONH—, —(CH₂)₃CH(OH)CH₂CONH—,—CH₂CH(OH)CH(OH)CH₂CONH—, —CH₂—CH═CH—CH(OH)CH₂CONH—, —(CH₂)₃CH(C₁₋₄alkoxy)CONH—, —(CH₂)₃CH(OCO(C₁₋₄ alkyl))CH₂CONH—, —(CH₂)₃C(O)CH₂CONH—,—CH₂O(CH₂)₃CONH—, —CH₂O(CH₂)₄CONH—, —CH₂NH(CH₂)₂CONH—,—CH₂NH(CH₂)₃CONH—, —(CH₂)₂N(C₁₋₄ alkyl)CH₂CONH—, —(CH₂)₂N(C₁₋₄alkyl)(CH₂)₂CONH—, —(CH₂)₅NHCO—, —CH₂—CH═CH—(CH₂)₂NHCO—, —(CH₂)₃OCONH—,—(CH₂)₄₀CONH—, —CH₂—CH═CH—CH₂OCONH—, —CH₂—CH═CH—CH₂NHCONH—,—(CH₂)₄SO₂NH—, —CH₂—CH═CH—CH₂SO₂NH—, —(CH₂)₄—CH═N—,

R^(1b) is independently selected from the group consisting of: H andhalogen;

R³ is independently selected from the group consisting of: H, halogen,C₁₋₄ alkyl, CN, CO₂(C₁₋₄ alkyl), CONH₂, CON(C₁₋₄ alkyl)₂, and C₃₋₆cycloalkyl; and

R⁶ is independently selected from the group consisting of: halogen, NH₂,CO₂H, CONH₂, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl),

In a 14th aspect, the present invention includes compounds of Formula(III), or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, a solvate, or a prodrug thereof, wherein:

L-Y is independently selected from the group consisting of: —(CH₂)₆—,—(CH₂)₇—, —(CH₂)₄CH(CO₂H)CH₂—, —(CH₂)₄CH(CO₂(C₁₋₄ alkyl))CH₂—,—(CH₂)₄CH(CONH₂)CH₂—, —(CH₂)₄CH(CONH(C₁₋₄ alkyl))CH₂—,—(CH₂)₄CH(CON(C₁₋₄ alkyl)₂)CH₂—, —CH₂—CH═CH—(CH₂)₃—, —CH₂—CH═CH—(CH₂)₄—,—CH₂CON(C₁₋₄ alkyl)(CH₂)₃—, —(CH₂)₅O—, —(CH₂)₆O—, —(CH₂)₃CH(C₁₋₄alkyl)(CH₂)₂O—, —(CH₂)₄CH(C₁₋₄ alkyl)CH₂O—, —CH₂NH(CH₂)₄O—,—CH₂—CH═CH—(CH₂)₃O—, —(CH₂)₅NH—, —(CH₂)₆NH—, —(CH₂)₃CH(C₁₋₄alkyl)CH₂NH—, —(CH₂)₄CH(C₁₋₄ alkyl)NH—, —(CH₂)₄CH(C₁₋₄ alkyl)CH₂NH—,—(CH₂)₄CH(CH₂OH)NH—, —(CH₂)₄CH(CH₂(C₁₋₄ alkoxy))NH—, —(CH₂)₄CH(CO₂H)NH—,—(CH₂)₄CH(CH₂CO₂H)NH—, —(CH₂)₄CH(CH₂CO₂(C₁₋₄ alkyl))NH—,—(CH₂)₄CH(CO₂(C₁₋₄ alkyl))NH—, —(CH₂)₄CH(CO₂CH₂CF₃)NH—,—(CH₂)₄CH(CO₂(CH₂)₂SO₂(C₁₋₄ alkyl))NH—, —(CH₂)₅CH(CO₂(C₁₋₄ alkyl))NH—,—(CH₂)₄CH(CONH₂)NH—, —(CH₂)₄CH(CONH(C₁₋₄ alkyl))NH—, —(CH₂)₄CH(CON(C₁₋₄alkyl)₂)NH—, —(CH₂)₄C(C₁₋₄ alkyl)(CO₂(C₁₋₄ alkyl))NH—,—(CH₂)₄C(CF₃)(CO₂(C₁₋₄ alkyl))NH—, —(CH₂)₃CH(C₁₋₄ alkyl)CH(CONH₂)NH—,—(CH₂)₄CH(CONH(C₁₋₄ alkoxy))NH—, —(CH₂)₄CH(CONH(OBn))NH—,—(CH₂)₄CH(CON(C₁₋₄ alkyl)(CH₂)₂O(C₁₋₄ alkyl))NH—, —(CH₂)₄CH(CON(C₁₋₄alkyl)(CH₂)₂N(C₁₋₄ alkyl)₂)NH—, —CH₂—CH═CH—(CH₂)₂NH—,—CH₂—CH═CH—(CH₂)₃NH—, —(CH₂)₄CH(CHF₂)NH—, —(CH₂)₄CH(CF₃)NH—,—(CH₂)₅CH(CF₃)NH—, —(CH₂)₃CF₂CH₂NH—, —CH₂—CH═CH—(CH₂)₂CH(CF₃)NH—,—CH₂CONH(CH₂)₂NH—, —CH₂CONH(CH₂)₃NH—, —(CH₂)₄CH(3-C₁₋₄alkyl-oxetan-3-yl)NH—, —(CH₂)₄CH(CO-pyrrolidin-1-yl)NH—,—(CH₂)₄CH(thiazol-4-yl)NH—, —(CH₂)₄CH(4-C₁₋₄ alkyl-thiazol-2-yl)NH—,—(CH₂)₄CH(1-C₁₋₄ alkyl-imidazol-2-yl)NH—, —(CH₂)₄CH(1-C₁₋₄alkyl-pyrazol-3-yl)NH—, —(CH₂)₄CH(1-C₁₋₄ alkyl-pyrazol-5-yl)NH—,—(CH₂)₄CH(1-C₁₋₄ alkyl-3-C₁₋₄ alkyl-pyrazol-5-yl)NH—, —(CH₂)₄CH(1-C₁₋₄alkyl-4-halo-pyrazol-3-yl)NH—, —CH₂—CH═CH—CH₂CH(1-C₁₋₄alkyl-pyrazol-5-yl)NH—, —(CH₂)₄N(CO₂(C₁₋₄ alkyl))CH₂—,—(CH₂)₄N(CH₂CO₂(C₁₋₄ alkyl))CH₂—, —(CH₂)₄CONH—, —(CH₂)₅CONH—,—(CH₂)₆CONH—, —(CH₂)₃CH(C₁₋₄ alkyl)CONH—, —(CH₂)₄CH(C₁₋₄ alkyl)CONH—,—(CH₂)₂CH(C₁₋₄ alkyl)CH₂CONH—, —(CH₂)₃CH(C₁₋₄ alkyl)CH₂CONH—,—(CH₂)₂CH(C₁₋₄ alkyl)(CH₂)₂CONH—, —(CH₂)₂—CH═CH—CONH—,—CH₂—CH═CH—CH₂CONH—, —CH₂—CH═CH—(CH₂)₂CONH—, —CH₂—CH═CH—(CH₂)₃CONH—,—CH₂—CH═CH—CH₂CH(C₁₋₄ alkyl)CONH—, —CH₂—CH═CH—CH(C₁₋₄ alkyl)CH₂CONH—,—CH₂—CH═C(C₁₋₄ alkyl)-(CH₂)₂CONH—, —(CH₂)₃CH(C₁₋₄ alkyl)CONH—,—(CH₂)₃CHFCONH—, —(CH₂)₃CF₂CONH—, —(CH₂)₄CF₂CONH—,—CH₂—CH═CH—CH₂CF₂CONH—, —(CH₂)₃CH(CF₃)CONH—, —CH₂CH(OH)(CH₂)₂CONH—,—(CH₂)₂CH(OH)CH₂CONH—, —(CH₂)₃CH(OH)CH₂CONH—, —CH₂CH(OH)CH(OH)CH₂CONH—,—CH₂—CH═CH—CH(OH)CH₂CONH—, —(CH₂)₃CH(C₁₋₄ alkoxy)CONH—,—(CH₂)₃CH(OCO(C₁₋₄ alkyl))CH₂CONH—, —(CH₂)₃C(O)CH₂CONH—,—CH₂O(CH₂)₃CONH—, —CH₂O(CH₂)₄CONH—, —CH₂NH(CH₂)₂CONH—,—CH₂NH(CH₂)₃CONH—, —(CH₂)₂N(C₁₋₄ alkyl)CH₂CONH—,—(C₂)₂(C₁₋₄alkyl)(CH₂)₂CONH—, —(CH₂)₅NHCO—, —CH₂—CH═CH—(CH₂)₂NHCO—,—CH₂—CH═CH—CH₂OCONH—, —(CH₂)₄OCONH—, —CH₂—CH═CH—CH₂NHCONH—,—(CH₂)₄SO₂NH—, —CH₂—CH═CH—CH₂SO₂NH—, —(CH₂)₄—CH═N—,

R^(1b) is independently selected from the group consisting of: H andhalogen;

R³ is independently selected from the group consisting of: H, halogen,C₁₋₄ alkyl, CN, CO₂(C₁₋₄ alkyl), CONH₂, CON(C₁₋₄ alkyl)₂, andcyclopropyl; and

R⁶ is independently selected from the group consisting of: halogen, NH₂,CO₂H, CONH₂, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), and

In a 15th aspect, the present invention includes compounds of Formula(III), or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, a solvate, or a prodrug thereof, wherein:

L-Y is independently selected from the group consisting of: —(CH₂)₆—,—(CH₂)₇—, —(CH₂)₄CH(CO₂H)CH₂—, —(CH₂)₄CH(CO₂Me)CH₂—,—(CH₂)₄CH(CONH₂)CH₂—, —(CH₂)₄CH(CONHMe)CH₂—, —(CH₂)₄CH(CON(Me)₂)CH₂—,—CH₂—CH═CH—(CH₂)₃—, —CH₂—CH═CH—(CH₂)₄—, —CH₂CON(CH₃)(CH₂)₃—,—(CH₂)₄N(CO₂Me)CH₂—, —(CH₂)₄N(CH₂CO₂Et)CH₂—, —(CH₂)₅O—, —(CH₂)₆O—,—(CH₂)₃CH(Me)(CH₂)₂O—, —(CH₂)₄CH(Me)CH₂O—, —CH₂NH(CH₂)₄O—,—CH₂—CH═CH—(CH₂)₃O—, —(CH₂)₅NH—, —(CH₂)₆NH—, —(CH₂)₃CH(Me)CH₂NH—,—(CH₂)₄CH(Me)NH—, —(CH₂)₄CH(Me)CH₂NH—, —(CH₂)₄CH(CH₂OH)NH—,—(CH₂)₄CH(CH₂OMe)NH—, —(CH₂)₄CH(CO₂H)NH—, —(CH₂)₄CH(CO₂Me)NH—,—(CH₂)₄CH(CO₂Et)NH—, —CH₂CONH(CH₂)₄NH—, —(CH₂)₄CH(CO₂(i-Pr))NH—,—(CH₂)₄CH(CO₂(t-Bu))NH—, —(CH₂)₄CH(CO₂CH₂CF₃)NH—,—(CH₂)₄CH(CO₂(CH₂)₂SO₂Me)NH—, —(CH₂)₅CH(CO₂Me)NH—,—(CH₂)₄CH(CH₂CO₂H)NH—, —(CH₂)₄CH(CH₂CO₂Me)NH—, —(CH₂)₄CH(CONH₂)NH—,—(CH₂)₄CH(CONH(Me))NH—, —(CH₂)₄CH(CONH(t-Bu))NH—,—(CH₂)₄CH(CON(Me)₂)NH—, —(CH₂)₄CH(CONH(OMe))NH—,—(CH₂)₄CH(CONH(OBn))NH—, —(CH₂)₄CH(CON(Me)(CH₂)₂OMe)NH—,—(CH₂)₄C(Me)(CO₂Me)NH—, —(CH₂)₄C(CF₃)(CO₂Me)NH—,—(CH₂)₃CH(Me)CH(CONH₂)NH—, —(CH₂)₄CH(CON(Me)(CH₂)₂N(Me)₂)NH—,—CH₂—CH═CH—(CH₂)₂NH—, —CH₂—CH═CH—(CH₂)₃NH—, —(CH₂)₄CH(CHF₂)NH—,—(CH₂)₄CH(CF₃)NH—, —(CH₂)₅CH(CF₃)NH—, —(CH₂)₃CF₂CH₂NH—.—CH₂—CH═CH—(CH₂)₂CH(CF₃)NH—, —CH₂CONH(CH₂)₂NH—, —CH₂CONH(CH₂)₃NH—.—(CH₂)₄CH(3-Me-oxetan-3-yl)NH—, —(CH₂)₄CH(CO-pyrrolidin-1-yl)NH—,—(CH₂)₄CH(thiazol-4-yl)NH—, —(CH₂)₄CH(4-Me-thiazol-2-yl)NH—,—(CH₂)₄CH(1-Me-imidazol-2-yl)NH—, —(CH₂)₄CH(1-Me-pyrazol-3-yl)NH—,—(CH₂)₄CH(1-(n-Pr)-pyrazol-3-yl)NH—, —(CH₂)₄CH(1-Me-pyrazol-5-yl)NH—,—(CH₂)₄CH(1,3-di-Me-pyrazol-5-yl)NH—,—(CH₂)₄CH(1-Me-4-Cl-pyrazol-3-yl)NH—,—CH₂—CH═CH—CH₂CH(1-Me-pyrazol-5-yl)NH—, —(CH₂)₄CONH—, —(CH₂)₅CONH—,—(CH₂)₆CONH—, —(CH₂)₃CH(Me)CONH—, —(CH₂)₄CH(Me)CONH—,—(CH₂)₂CH(Me)CH₂CONH—, —(CH₂)₃CH(Me)CH₂CONH—, —(CH₂)₂CH(Me)(CH₂)₂CONH—,—(CH₂)₂—CH═CH—CONH—, —CH₂—CH═CH—CH₂CONH—, —CH₂—CH═CH—(CH₂)₂CONH—,—CH₂—CH═CH—(CH₂)₃CONH—, —CH₂—CH═CH—CH₂CH(Me)CONH—,—CH₂—CH═CHCH(Me)CH₂CONH—, —CH₂—CH═CHCH(Et)CH₂CONH—, —CH₂—CH═C(Me)-(CH₂)₂CONH—, —(CH₂)₃CH(Et)CONH—, —(CH₂)₃CH(i-Pr)CONH—,—(CH₂)₃CHFCONH—, —(CH₂)₃CF₂CONH—, —(CH₂)₄CF₂CONH—,—CH₂—CH═CH—CH₂CF₂CONH—, —(CH₂)₃CH(CF₃)CONH—, —CH₂CH(OH)(CH₂)₂CONH—,—(CH₂)₂CH(OH)CH₂CONH—, —(CH₂)₃CH(OH)CH₂CONH—, —CH₂CH(OH)CH(OH)CH₂CONH—,—CH₂—CH═CH—CH(OH)CH₂CONH—, —(CH₂)₃CH(OMe)CONH—,—(CH₂)₃CH(OCOMe)CH₂CONH—, —(CH₂)₃C(O)CH₂CONH—, —CH₂O(CH₂)₃CONH—,—CH₂O(CH₂)₄CONH—, —CH₂NH(CH₂)₂CONH—, —CH₂NH(CH₂)₃CONH—,—(CH₂)₂N(Me)CH₂CONH—, —(CH₂)₂N(Me)(CH₂)₂CONH—, —(CH₂)₅NHCO—,—CH₂—CH═CH—(CH₂)₂NHCO—, —CH₂—CH═CH—CH₂OCONH—, —(CH₂)₄OCONH—,—CH₂—CH═CH—CH₂NHCONH—, —(CH₂)₄SO₂NH—, —CH₂—CH═CH—CH₂SO₂NH—,—(CH₂)₄—CH═N—,

R^(1b) is independently selected from the group consisting of: H and F;

R³ is independently selected from the group consisting of: H, F, Cl, Br,CH₃, CN, CO₂Me, CO₂Et, CONH₂, CONMe₂, and cyclopropyl; and

R⁶ is independently selected from the group consisting of: F, NH₂, CO₂H,CONH₂, —NHCO₂Me, —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂OMe, —NHCO₂(CH₂)₂OEt,—NHCO₂CH₂CH(Et)OMe, and

In a 16th aspect, the present invention includes compounds of Formula(III), or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, a solvate, or a prodrug thereof, wherein:

L-Y is independently selected from the group consisting of: —(CH₂)₆—,—(CH₂)₇—, —(CH₂)₄CH(CO₂H)CH₂—, —(CH₂)₄CH(CO₂(C₁₋₄ alkyl))CH₂—,—(CH₂)₄CH(CONH₂)CH₂—, —(CH₂)₄CH(CONH(C₁₋₄ alkyl))CH₂—,—(CH₂)₄CH(CON(C₁₋₄ alkyl)₂)CH₂—, —CH₂—CH═CH—(CH₂)₄—, —(CH₂)₄N(CO₂(C₁₋₄alkyl))CH₂—, —(CH₂)₆O—, —(CH₂)₃CH(C₁₋₄ alkyl)(CH₂)₂O—, —CH₂NH(CH₂)₄O—,—(CH₂)₅NH—, —(CH₂)₆NH—, —(CH₂)₄CH(C₁₋₄ alkyl)NH—, —(CH₂)₃CH(C₁₋₄alkyl)CH₂NH—, —(CH₂)₄CH(C₁₋₄ alkyl)CH₂NH—, —(CH₂)₄CH(CH₂OH)NH—,—(CH₂)₄CH(CH₂(C₁₋₄ alkoxy))NH—, —(CH₂)₄CH(CO₂H)NH—,—(CH₂)₄CH(CH₂CO₂H)NH—, —(CH₂)₄CH(CH₂CO₂(C₁₋₄ alkyl))NH—,—(CH₂)₄CH(CO₂(C₁₋₄ alkyl))NH—, —(CH₂)₄CH(CO₂CH₂CF₃)NH—,—(CH₂)₄CH(CO₂(CH₂)₂SO₂(C₁₋₄ alkyl))NH—, —(CH₂)₅CH(CO₂(C₁₋₄ alkyl))NH—,—(CH₂)₄CH(CONH₂)NH—, —(CH₂)₄CH(CONH(C₁₋₄ alkyl))NH—, —(CH₂)₄CH(CON(C₁₋₄alkyl)₂)NH—, —(CH₂)₄CH(CONH(C₁₋₄alkoxy))NH—, —(CH₂)₄CH(CONH(OBn))NH—,—(CH₂)₄CH(CON(C₁₋₄ alkyl)(CH₂)₂O(C₁₋₄ alkyl))NH—, —(CH₂)₄CH(CON(C₁₋₄alkyl)(CH₂)₂N(C₁₋₄ alkyl)₂)NH—, —CH₂—CH═CH—(CH₂)₂NH—,—CH₂—CH═CH—(CH₂)₃NH—, —(CH₂)₄CH(CHF₂)NH—, —(CH₂)₄CH(CF₃)NH—,—(CH₂)₃CF₂CH₂NH—, —CH₂—CH═CH—(CH₂)₂CH(CF₃)NH—, —(CH₂)₄CH(3-C₁₋₄alkyl-oxetan-3-yl)NH—, —(CH₂)₄CH(CO-pyrrolidin-1-yl)NH—,—(CH₂)₄CH(thiazol-4-yl)NH—, —(CH₂)₄CH(4-C₁₋₄ alkyl-thiazol-2-yl)NH—,—(CH₂)₄CH(1-C₁₋₄ alkyl-imidazol-2-yl)NH—, —(CH₂)₄CH(1-C₁₋₄alkyl-pyrazol-3-yl)NH—, —(CH₂)₄CH(1-C₁₋₄ alkyl-pyrazol-5-yl)NH—,—(CH₂)₄CH(1-C₁₋₄ alkyl-3-C₁₋₄ alkyl-pyrazol-5-yl)NH—, —(CH₂)₄CH(1-C₁₋₄alkyl-4-halo-pyrazol-3-yl)NH—, —(CH₂)₄CONH—, —(CH₂)₅CONH—, —(CH₂)₆CONH—,—(CH₂)₃CH(C₁₋₄ alkyl)CONH—, —(CH₂)₄CH(C₁₋₄ alkyl)CONH—, —(CH₂)₂CH(C₁₋₄alkyl)CH₂CONH—, —(CH₂)₃CH(C₁₋₄ alkyl)CH₂CONH—, —(CH₂)₂CH(C₁₋₄alkyl)(CH₂)₂CONH—, —(CH₂)₂—CH═CH—CONH—, —CH₂—CH═CH—CH₂CONH—,—CH₂—CH═CH—(CH₂)₂CONH—, —CH₂—CH═CH—(CH₂)₃CONH—, —CH₂—CH═CH—CH₂CH(C₁₋₄alkyl)CONH—, —CH₂—CH═CH—CH(C₁₋₄ alkyl)CH₂CONH—, —CH₂—CH═C(C₁₋₄alkyl)-(CH₂)₂CONH—, —(CH₂)₃CH(C₁₋₄ alkyl)CONH—, —(CH₂)₃CHFCONH—,—(CH₂)₃CF₂CONH—, —(CH₂)₄CF₂CONH—, —CH₂—CH═CH—CH₂CF₂CONH—,—(CH₂)₃CH(CF₃)CONH—, —CH₂CH(OH)(CH₂)₂CONH—, —(CH₂)₂CH(OH)CH₂CONH—,—(CH₂)₃CH(OH)CH₂CONH—, —CH₂CH(OH)CH(OH)CH₂CONH—,—CH₂—CH═CH—CH(OH)CH₂CONH—, —(CH₂)₃CH(C₁₋₄ alkoxy)CONH—,—(CH₂)₃CH(OCO(C₁₋₄ alkyl))CH₂CONH—, —(CH₂)₃C(O)CH₂CONH—,—CH₂O(CH₂)₃CONH—, —CH₂O(CH₂)₄CONH—, —CH₂NH(CH₂)₂CONH—,—CH₂NH(CH₂)₃CONH—, —(CH₂)₂N(C₁₋₄ alkyl)CH₂CONH—, —(CH₂)₂N(C₁₋₄alkyl)(CH₂)₂CONH—, —(CH₂)₅NHCO—, —CH₂—CH═CH—(CH₂)₂NHCO—,—CH₂—CH═CH—CH₂OCONH—, —(CH₂)₄OCONH—, —CH₂—CH═CH—CH₂NHCONH—,—(CH₂)₄SO₂NH—, —CH₂—CH═CH—CH₂SO₂NH—, —(CH₂)₄—CH═N—,

R^(1b) is independently selected from the group consisting of: H andhalogen;

R³ is independently selected from the group consisting of: H, halogen,C₁₋₄ alkyl, CN, CO₂(C₁₋₄ alkyl), CONH₂, CON(C₁₋₄ alkyl)₂, andcyclopropyl; and

R⁶ is independently selected from the group consisting of: F, NH₂, CO₂H,—NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), and

In a 17th aspect, the present invention includes compounds of Formula(III), or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, a solvate, or a prodrug thereof, wherein:

L-Y is independently selected from the group consisting of: —(CH₂)₆—,—(CH₂)₇—, —(CH₂)₄CH(CO₂H)CH₂—, —(CH₂)₄CH(CO₂Me)CH₂—,—(CH₂)₄CH(CONH₂)CH₂—, —(CH₂)₄CH(CONHMe)CH₂—, —(CH₂)₄CH(CON(Me)₂)CH₂—,—CH₂—CH═CH—(CH₂)₄—, —(CH₂)₄N(CO₂Me)CH₂—, —(CH₂)₆O—,—(CH₂)₃CH(Me)(CH₂)₂O—, —CH₂NH(CH₂)₄O—, —(CH₂)₅NH—, —(CH₂)₆NH—,—(CH₂)₄CH(Me)NH—, —(CH₂)₃CH(Me)CH₂NH—, —(CH₂)₄CH(Me)CH₂NH—,—(CH₂)₄CH(CH₂OH)NH—, —(CH₂)₄CH(CH₂OMe)NH—, —(CH₂)₄CH(CO₂H)NH—,—(CH₂)₄CH(CO₂Me)NH—, —(CH₂)₄CH(CO₂Et)NH—, —(CH₂)₄CH(CO₂(i-Pr))NH—,—(CH₂)₄CH(CO₂(t-Bu))NH—, —(CH₂)₄CH(CO₂CH₂CF₃)NH—,—(CH₂)₄CH(CO₂(CH₂)₂SO₂Me)NH—, —(CH₂)₅CH(CO₂Me)NH—,—(CH₂)₄CH(CH₂CO₂H)NH—, —(CH₂)₄CH(CH₂CO₂Me)NH—, —(CH₂)₄CH(CONH₂)NH—,—(CH₂)₄CH(CONH(Me))NH—, —(CH₂)₄CH(CONH(t-Bu))NH—,—(CH₂)₄CH(CON(Me)₂)NH—, —(CH₂)₄CH(CONH(OMe))NH—,—(CH₂)₄CH(CONH(OBn))NH—, —(CH₂)₄CH(CON(Me)(CH₂)₂OMe)NH—,—(CH₂)₄CH(CON(Me)(CH₂)₂N(Me)₂)NH—, —CH₂—CH═CH—(CH₂)₂NH—,—CH₂—CH═CH—(CH₂)₃NH—, —(CH₂)₄CH(CHF₂)NH—, —(CH₂)₄CH(CF₃)NH—,—(CH₂)₃CF₂CH₂NH—, —CH₂—CH═CH—(CH₂)₂CH(CF₃)NH—,—(CH₂)₄CH(3-Me-oxetan-3-yl)NH—, —(CH₂)₄CH(CO-pyrrolidin-1-yl)NH—,—(CH₂)₄CH(thiazol-4-yl)NH—, —(CH₂)₄CH(4-Me-thiazol-2-yl)NH—,—(CH₂)₄CH(1-Me-imidazol-2-yl)NH—, —(CH₂)₄CH(1-Me-pyrazol-3-yl)NH—,—(CH₂)₄CH(1-(n-Pr)-pyrazol-3-yl)NH—, —(CH₂)₄CH(1-Me-pyrazol-5-yl)NH—,—(CH₂)₄CH(1,3-di-Me-pyrazol-5-yl)NH—,—(CH₂)₄CH(1-Me-4-Cl-pyrazol-3-yl)NH—, —(CH₂)₄N(CO₂Me)CH₂—, —(CH₂)₄CONH—,—(CH₂)₅CONH—, —(CH₂)₆CONH—, —(CH₂)₃CH(Me)CONH—, —(CH₂)₄CH(Me)CONH—,—(CH₂)₂CH(Me)CH₂CONH—, —(CH₂)₃CH(Me)CH₂CONH—, —(CH₂)₂CH(Me)(CH₂)₂CONH—,—(CH₂)₂—CH═CH—CONH—, —CH₂—CH═CH—CH₂CONH—, —CH₂—CH═CH—(CH₂)₂CONH—,—CH₂—CH═CH—(CH₂)₃CONH—, —CH₂—CH═CH—CH₂CH(Me)CONH—,—CH₂—CH═CH—CH(Me)CH₂CONH—, —CH₂—CH═CHCH(Et)CH₂CONH—,—CH₂—CH═C(Me)-(CH₂)₂CONH—, —(CH₂)₃CH(Me)CONH—, —(CH₂)₃CH(Et)CONH—,—(CH₂)₃CH(i-Pr)CONH—, —(CH₂)₃CHFCONH—, —(CH₂)₃CF₂CONH—, —(CH₂)₄CF₂CONH—,—CH₂—CH═CH—CH₂CF₂CONH—, —(CH₂)₃CH(CF₃)CONH—, —CH₂CH(OH)(CH₂)₂CONH—,—(CH₂)₂CH(OH)CH₂CONH—, —(CH₂)₃CH(OH)CH₂CONH—, —CH₂CH(OH)CH(OH)CH₂CONH—,—CH₂—CH═CH—CH(OH)CH₂CONH—, —(CH₂)₃CH(OMe)CONH—,—(CH₂)₃CH(OCOMe)CH₂CONH—, —(CH₂)₃C(O)CH₂CONH—, —CH₂O(CH₂)₃CONH—,—CH₂O(CH₂)₄CONH—, —CH₂NH(CH₂)₂CONH—, —CH₂NH(CH₂)₃CONH—,—(CH₂)₂N(Me)CH₂CONH—, —(CH₂)₂N(Me)(CH₂)₂CONH—, —(CH₂)₅NHCO—,—CH₂—CH═CH—(CH₂)₂NHCO—, —CH₂—CH═CH—CH₂OCONH—, —(CH₂)₄OCONH—,—CH₂—CH═CH—CH₂NHCONH—, —(CH₂)₄SO₂NH—, —CH₂—CH═CH—CH₂SO₂NH—,—(CH₂)₄—CH═N—,

R^(1b) is independently selected from the group consisting of: H and F;

R³ is independently selected from the group consisting of: H, F, Cl, Br,CH₃, CN, CO₂Me, CO₂Et, CONH₂, CONMe₂, and cyclopropyl; and

R⁶ is independently selected from the group consisting of: F, NH₂, CO₂H,—NHCO₂Me, —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂OMe, —NHCO₂(CH₂)₂OEt,—NHCO₂CH₂CH(Et)OMe, and

In an 18th aspect, the present invention includes compounds of Formula(IV):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, within the scope of any one of the firstto tenth aspects, wherein:

is independently selected from the group consisting of:

L₁ is independently selected from the group consisting of: a bond,—CH₂CH₂— and —CH═CH—;

L is independently selected from the group consisting of:—CH₂—CH═CH—CH₂—, —CH₂—CH═CH—(CH₂)₂—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₃CH(C₁₋₄alkyl)-, —CH₂—CH═CH—CH₂CH(CF₃)—, —(CH₂)₄CH(CF₃)—, —(CH₂)₄CH(CH₂OH)—,—(CH₂)₄CH(CO₂H)—, —(CH₂)₄CH(CO₂(C₁₋₄ alkyl))-, —CH₂CONH(CH₂)₂—,—(CH₂)₄CH(CO₂(CH₂)₂O(C₁₋₄ alkyl))-, —(CH₂)₄CH(CH₂NH(CH₂)₂O(C₁₋₄alkyl))-, —(CH₂)₄CH(CO₂(CH₂)₂N(C₁₋₄ alkyl)₂)-, —(CH₂)₄CH(CON(C₁₋₄alkyl)(CH₂)₂O(C₁₋₄ alkyl))-, —(CH₂)₄CH(CON(C₁₋₄ alkyl)(CH₂)₂N(C₁₋₄alkyl)₂)-,

Y is independently —CONH—, O, or NH;

R¹ is, independently at each occurrence, selected from: halogen, CN,OCF₃, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), NH₂,—C(═NH)NH₂, —C(O)NH₂, and —CH₂NH₂;

R² is independently a 5-membered heterocycle selected from: pyrazolyl,imidazolyl, triazolyl, and tetrazolyl;

R³ is independently selected from the group consisting of: H, halogen,and C₁₋₄ alkyl; and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: H, halogen, CN, —NHCO₂(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl), CO₂H, and CONH₂.

In a 19th aspect, the present invention includes compounds of Formula(IVa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, within the scope of the 18th aspect,wherein:

is independently selected from the group consisting of:

Y is independently —CONH— or NH;

R³ is independently selected from the group consisting of: H, F, Cl, andC₁₋₄ alkyl; and

R⁶ is independently selected from the group consisting of: F,—NHCO₂(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄ alkyl), CO₂H, CONH₂, and—NHCO₂(CH₂)₂O(C₁₋₄ alkyl).

In a 20th aspect, the present invention includes compounds of Formula(V):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, within the scope of the first, second orthird aspect, wherein:

ring B is independently selected from the group consisting of: imidazoleand pyridine; and

R¹ is independently selected from the group consisting of: C₁₋₄ alkyland CH₂NH₂.

In another aspect, the present invention includes compounds of Formula(V): or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,a solvate, or a prodrug thereof, wherein:

ring B is independently selected from the group consisting of:

L is independently selected from the group consisting of:—CH₂—CH═CH—(CH₂)₂—, —CH₂—CH═CH—CH₂CF₂—, —(CH₂)₄—, and —(CH₂)₄CH(CF₃)—;

Y is independently selected from the group consisting of: —CH₂—, —CONH—,and NH;

R³ is independently selected from the group consisting of: H, F, Cl, andMe; and

R^(6a) is independently selected from the group consisting of: H and—NHCO₂Me.

In a 21st aspect, the present invention provides a compound selectedfrom the exemplified examples or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof.

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds within the scope of the 24th aspect.

In another aspect, the present invention provides compounds of Formula(I), (II), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,within the scope of the fourth aspect, wherein:

is independently selected from the group consisting of:

In another aspect wherein:

is independently selected from the group consisting of:

In another aspect, wherein:

In another aspect, the present invention provides compounds of Formula(I), (II), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,within the scope of the fourth aspect, wherein:

is independently selected from the group consisting of:

In another aspect wherein:

is independently selected from the group consisting of:

In another aspect wherein:

is independently selected from the group consisting of:

In another aspect wherein:

In another aspect wherein:

In another aspect, the present invention includes compounds of Formula(I), (II), (IIa), or (IIb), a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,within the scope of any of the above aspects, wherein:

R² is independently a 5-membered heterocycle substituted with 0-1R^(2a), wherein said heterocycle is selected from: pyrazolyl,imidazolyl, triazolyl, and tetrazolyl; and

R^(2a) is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, NH₂, CH₂OH, CO₂H, C₁₋₄ alkyl, —CONH₂,—CONH(C₁₋₄ alkyl), and —CON(C₁₋₄ alkyl)₂.

In another aspect, the present invention includes compounds of Formula(I), (II), (IIa), or (IIb), a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,within the scope of any of the above aspects, wherein:

R² is independently selected from the group consisting of: triazolyl andtetrazolyl.

In another embodiment, ring A is independently selected from the groupconsisting of: phenyl, cyclohexyl, and 5,6,7,8-tetrahydroisoquinolinyl.

In another embodiment, ring A is phenyl.

In another embodiment, ring A is cyclohexyl.

In another embodiment, ring A is tetrahydroisoquinoline.

In another aspect, ring A is

wherein R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), CN,CH₂F, CHF₂, OCHF₂, NH₂, N(C₁₋₄ alkyl)₂, —CH₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl),and —C(═NH)NH₂.

In another aspect, ring A is

is independently selected from the group consisting of:

In another embodiment, ring B is independently selected from the groupconsisting of: imidazole, oxadiazole, pyridine, pyridazine, and benzene.

In another embodiment,

is independently selected from the group consisting of:

In another embodiment,

is independently selected from the group consisting of:

In another embodiment,

In another embodiment,

In another embodiment,

is independently selected from the group consisting of:

In another embodiment,

is independently selected from the group consisting of:

In another embodiment,

In another embodiment,

In another embodiment,

In another embodiment,

In another embodiment, L₁ is independently selected from the groupconsisting of: a bond, —CH₂CH₂—, —CH═CH—, —C(Me)=CH—, —C≡C—, and—CH₂NH—.

In another embodiment, L₁ is independently selected from the groupconsisting of: a bond, —CH₂CH₂—, —CH═CH—, and —C(Me)=CH.

In another embodiment, L₁ is independently selected from the groupconsisting of: a bond, —CH₂CH₂— and —CH═CH—.

In another embodiment, L₁ is a bond.

In another embodiment, L₁ is —CH═CH—.

In another embodiment, L is independently selected from the groupconsisting of: C₃₋₇ alkylene and C₃₋₇ alkenylene; wherein said alkyleneand alkenylene are substituted with 0-2 R⁷ and optionally one or two ofthe carbon atoms of said alkylene and alkenylene may be replaced by O,NH, N(C₁₋₄ alkyl), CONH, NHCO, or CON(C₁₋₄ alkyl).

In another embodiment, L is independently selected from the groupconsisting of: C₃₋₇ alkylene and C₄₋₇ alkenylene; wherein said alkyleneand alkenylene are optionally substituted with 1-2 R⁷; optionally one ortwo of the carbon atoms of said alkylene and alkenylene may be replacedby O, NH, N(C₁₋₄ alkyl), CONH, or CON(C₁₋₄ alkyl).

In another embodiment, L is C₃₋₇ alkylene, wherein said alkylene isoptionally substituted with 1-2 R⁷; optionally one or two of the carbonatoms of said alkylene may be replaced by O, NH, N(C₁₋₄ alkyl), CONH, orCON(C₁₋₄ alkyl).

In another embodiment, L is C₄₋₇ alkenylene, wherein said alkenylene isoptionally substituted with 1-2 R⁷; optionally one or two of the carbonatoms of said alkenylene may be replaced by O, NH, N(C₁₋₄ alkyl), CONH,or CON(C₁₋₄ alkyl).

In another embodiment, Y is independently selected from the groupconsisting of: —CH₂—, O, NH, N(C₁₋₄ alkyl), —NHCO—, —CONH—, —CONHCH₂—,—CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —NHCONH—, and —SO₂NH—.

In another embodiment, Y is independently selected from the groupconsisting of: —CH₂—, O, NH, NMe, —CONH—, —NHCO—, —CONHCH₂—, —CONMeCH₂—,—OCONH—, —NHCONH—, and —SO₂NH—.

In another embodiment, Y is —CONH—.

In another embodiment, R¹ is, independently at each occurrence, selectedfrom the group consisting of: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, OH, CH₂F, CHF₂, CF₃, OCH₂F, OCHF₂, OCF₃, CN, NH₂, NH(C₁₋₄alkyl)₂, N(C₁₋₄ alkyl)₂, CO₂(C₁₋₄ alkyl), CO(C₁₋₄ alkyl), —OCH₂CO₂H,—CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄ alkyl), —SO₂NH₂, and—C(═NH)NH₂.

In another embodiment, R¹ is, independently at each occurrence, selectedfrom the group consisting of: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, OH, CHF₂, CF₃, OCF₃, CN, NH₂, CO₂(C₁₋₄ alkyl), CO(C₁₋₄alkyl), —OCH₂CO₂H, —CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl), —SO₂NH₂, and—C(═NH)NH₂.

In another embodiment, R¹ is, independently at each occurrence, selectedfrom: halogen, CN, OH, CH₂F, CHF₂, CF₃, OCH₂F, OCHF₂, OCF₃, C₁₋₄ alkyl,C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), NH₂, NH(C₁₋₄ alkyl)₂, N(C₁₋₄ alkyl)₂,—C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl), and —SO₂NH₂.

In another embodiment, R¹ is, independently at each occurrence, selectedfrom: halogen, CN, OH, OCF₃, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CO(C₁₋₄alkyl), NH₂, —C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, and —SO₂NH₂.

In another embodiment, R¹ is selected from the group consisting of:halogen, C₁₋₄ alkyl, CHF₂, and CO(C₁₋₄ alkyl).

In another embodiment, R² is a 5-membered heterocycle substituted with0-1 R^(2a), wherein said heterocycle is independently selected from:pyrazolyl, imidazolyl, triazolyl, and tetrazolyl.

In another embodiment, R² is independently selected from the groupconsisting of: triazolyl and tetrazolyl.

In another embodiment, R² is tetrazolyl.

In another embodiment, R³ is independently selected from the groupconsisting of: H, halogen, C₁₋₄ alkyl, CN, CO₂(C₁₋₄ alkyl), CONH₂, andcyclopropyl.

In another embodiment, R³ is independently selected from the groupconsisting of: H, C₁₋₄ alkyl, and halogen.

In another embodiment, R³ is independently selected from the groupconsisting of: H and halogen.

In another embodiment, R³ is independently selected from the groupconsisting of: H and Cl.

In another embodiment, R³ is H.

In another embodiment, R³ is Cl.

In another embodiment, R⁴ is H.

In another embodiment, R⁵ is, independently at each occurrence, selectedfrom the group consisting of: H and C₁₋₄ alkyl.

In another embodiment, R⁵ is, independently at each occurrence, selectedfrom the group consisting of: H and methyl.

In another embodiment, R⁶ is, independently at each occurrence, selectedfrom the group consisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H,CO₂(C₁₋₄ alkyl), —CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl),—(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl),—NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —C(O)NH(CH₂)₂O(C₁₋₄ alkyl), CONH₂,CONH(C₁₋₄alkyl), CON(C₁₋₄alkyl)₂, —CH₂CONH₂,

In another embodiment, R⁶ is, independently at each occurrence, selectedfrom the group consisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H,CO₂(C₁₋₄ alkyl), —CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl),—(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl),—NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), and —CONH₂.

In another embodiment, R⁶ is, independently at each occurrence, selectedfrom the group consisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H,CO₂(C₁₋₄ alkyl), —CH₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄alkyl), —NHCO₂(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄ alkyl), —CONH₂,—NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂CH₂CO₂H,—NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl),

In another embodiment, R⁶ is, independently at each occurrence, selectedfrom the group consisting of: halogen, NH₂, CO₂H, CO₂(C₁₋₄ alkyl),CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, —NHCO₂(C₁₋₄ alkyl),—CH₂NHCO₂(C₁₋₄ alkyl), —NHCO₂CH₂CO₂H, —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl),

In another embodiment, R⁶ is, independently at each occurrence, selectedfrom the group consisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H,CO₂(C₁₋₄ alkyl), —CH₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄alkyl), —NHCO₂(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄ alkyl), and —CONH₂.

In another embodiment, R⁶ is, independently at each occurrence, selectedfrom the group consisting of: halogen, CO₂H, CO₂(C₁₋₄ alkyl), NH₂,NHCO₂(C₁₋₄ alkyl), and —CH₂NHCO₂(C₁₋₄ alkyl).

In another embodiment, R⁶ is, independently at each occurrence, isselected from the group consisting of: halogen, NH₂, NHCO₂(C₁₋₄ alkyl),and —CH₂NHCO₂(C₁₋₄ alkyl).

In another embodiment, R⁶ is, independently at each occurrence, isselected from the group consisting of: F, NH₂, NHCO₂Me, and —CH₂NHCO₂Me.

In another embodiment, R^(6a) is independently selected from the groupconsisting of: H, halogen, NH₂, CO₂H, CONH₂, —NHCO₂(C₁₋₄ alkyl),—NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄alkyl),

In another embodiment, R^(6a) is independently selected from the groupconsisting of: H, halogen, NH(C₁₋₄ alkyl), and NHCO₂(C₁₋₄ alkyl).

In another embodiment, R^(6a) is independently selected from the groupconsisting of: H, halogen, and NHCO₂(C₁₋₄ alkyl).

In another embodiment, R^(6a) is independently selected from the groupconsisting of: H, F, and NHCO₂Me.

In another embodiment, R⁷ is, independently at each occurrence, selectedfrom the group consisting of: halogen, OH, CHF₂, CF₃, C₁₋₄ alkoxy,CH₂OH, CH₂O(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), CH₂CO₂H, CH₂CO₂(C₁₋₄alkyl), CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, —OCO(C₁₋₄ alkyl),—CON(C₁₋₄ alkyl)(CH₂)₂N(C₁₋₄ alkyl)₂, —CONH(C₁₋₄ alkoxy), C₁₋₄ alkyl,and —(CO)₀₋₁-(4- to 6-membered heterocycle comprising carbon atoms and1-4 heteroatoms selected from N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p));wherein said heterocycle is substituted with 0-2 R⁸.

In another embodiment, R⁷ is independently selected from the groupconsisting of: halogen, C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂.

In another embodiment, R⁷ is independently selected from the groupconsisting of: halogen, and C₁₋₄ alkyl.

In another aspect, the present invention provides, inter alia, acompound of Formula (I-1):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, wherein:

ring A is a C₃₋₁₀ carbocycle or a 5- to 10-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p);

ring B is a benzene ring or a 5- to 6-membered heteroaryl comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p);

ring C is a benzene ring or a 5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p);

L₁ is selected from the group consisting of: a bond, —CHR⁵CHR⁵—,—CR⁵═CR⁵—, —C≡C—, —OCH₂—, —CHR⁵NH—, —CH₂O—, —SCH₂—, —SO₂CH₂—, —CH₂NH—,and —CR⁵R⁵—;

L is selected from the group consisting of: C₃₋₈ alkylene, C₄₋₈alkenylene and C₄₋₈ alkynylene; wherein said alkylene, alkenylene andalkynylene are optionally substituted with 1-2 R⁷; optionally one ormore of the carbon atoms of said alkylene and alkenylene may be replacedby O, S, NH, N(C₁₋₄ alkyl), CO, CONH, NHCO, OCONH, SO₂NH, or CON(C₁₋₄alkyl);

Y is selected from the group consisting of: O, S, NH, N(C₁₋₄ alkyl),CH₂, CH(C₁₋₄ alkyl), C(C₁₋₄ alkyl)₂, —CONH—, —NHCO—, —CONHCH₂—,—CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —OCON(C₁₋₄ alkyl)-, —NHCONH—, —SO₂NH—,—NHCO₂—, and —NHSO₂—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, OH,CHF₂, CF₃, OCF₃, CN, NH₂, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂,—CONH₂, —CONH(C₁₋₄ alkyl), —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, and —C(═NH)NH₂;

R² is a 5- to 7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(2a);

R^(2a) is, independently at each occurrence, selected from the groupconsisting of: C₁₋₄ alkyl, —CH₂OH, C₁₋₄ alkoxy, OH, CF₃, OCF₃, CN, NH₂,CO₂H, CO₂(C₁₋₄ alkyl), COC₁₋₄ alkyl, —CONH₂, —CONH(C₁₋₄ alkyl),—CON(C₁₋₄ alkyl)₂, —SO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), and—SO₂N(C₁₋₄ alkyl)₂;

R³ is selected from the group consisting of: H, halogen, OH, NH₂, CF₃,C₁₋₄ alkyl, C₁₋₄ alkoxy, —CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), —C(O)NH₂,—C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, and —CH₂CO₂H;

R⁴ is selected from the group consisting of: H and C₁₋₄ alkyl;

R⁵ is, independently at each occurrence, selected from the groupconsisting of: H, halogen, OH, and C₁₋₄ alkyl;

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂,—CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂,—NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂,and —CH₂CONH₂;

R⁷ is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, NH₂, —CH₂NH₂, CHF₂, CF₃, —NH(C₁₋₄ alkyl),—N((C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and C₁₋₄ alkyl; and

p is, independently at each occurrence, selected from the groupconsisting of: 0, 1, and 2.

In another aspect, the present invention provides compounds of Formula(I-1), or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, a solvate, or a prodrug thereof, wherein:

ring A is a 6-membered carbocycle or 5,6,7,8-tetrahydroisoquinoline;

ring B is selected from the group consisting of: imidazole, oxadiazole,pyridine, pyridazine, pyrimidine, and benzene; and

ring C is selected from the group consisting of: benzene and pyridine.

In another aspect, the present invention provides compounds of Formula(Ia), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,a solvate, or a prodrug thereof, wherein:

ring A is selected from the group consisting of: benzene, cyclohexane,and 5,6,7,8-tetrahydroisoquinoline;

is selected from the group consisting of:

is selected from the group consisting of:

In another aspect, the present invention provides compounds of Formula(II-1)

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, wherein:

is selected from the group consisting of:

L₁ is selected from the group consisting of: a bond, —CHR⁵CHR⁵—,—CR⁵═CHR⁵—, —C≡C—, —OCH₂—, —CHR⁵NH—, —CH₂O—, —SCH₂—, —SO₂CH₂—, —CH₂NH—,and —CR⁵R⁵—;

L is selected from the group consisting of: C₃₋₈ alkylene and C₄₋₈alkenylene; wherein said alkylene and alkenylene are optionallysubstituted with 1-2 R⁷; optionally one or two of the carbon atoms ofsaid alkylene and alkenylene may be replaced by O, S, NH, N(C₁₋₄ alkyl),CONH—, or CON(C₁₋₄ alkyl);

Y is selected from the group consisting of: CH₂, CH(C₁₋₄ alkyl), C(C₁₋₄alkyl)₂, O, S, NH, N(C₁₋₄ alkyl), —CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄alkyl)CH₂—, —OCONH—, —OCON(C₁₋₄ alkyl)-, —NHCONH—, and —SO₂NH—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, OH,CHF₂, CF₃, OCF₃, CN, NH₂, CO₂(C₁₋₄ alkyl), CO(C₁₋₄ alkyl), —OCH₂CO₂H,—CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl), —SO₂NH₂, and —C(═NH)NH₂;

R² is a 5- to 6-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(2a);

R^(2a) is, independently at each occurrence, selected from the groupconsisting of: C₁₋₄ alkyl, —CH₂OH, C₁₋₄ alkoxy, OH, CF₃, CN, NH₂, CO₂H,CO₂(C₁₋₄ alkyl), COC₁₋₄ alkyl, —CONH₂, —CONH(C₁₋₄ alkyl), and —CON(C₁₋₄alkyl)₂;

R³ is selected from the group consisting of: H, halogen, OH, NH₂, CF₃,C₁₋₄ alkyl, C₁₋₄ alkoxy, —CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), —C(O)NH₂,—C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, and —CH₂CO₂H;

R⁴ is selected from the group consisting of: H and C₁₋₄ alkyl;

R⁵ is, independently at each occurrence, selected from the groupconsisting of: H, halogen, OH, and C₁₋₄ alkyl;

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂,—CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂,—NHSO₂(C₁₋₄ alkyl), —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—C(O)NH(CH₂)₂O(C₁₋₄ alkyl), and —CH₂CONH₂;

R⁷ is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, CF₃, C₁₋₄ alkoxy and C₁₋₄ alkyl; and

p is, independently at each occurrence, selected from the groupconsisting of: 0, 1, and 2.

In another aspect, the present invention provides compounds of Formula(I), (II), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

is selected from the group consisting of:

In another aspect, the present invention provides compounds of Formula(I-1), (II-1), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

In another aspect, the present invention provides compounds of Formula(I-1), (II-1), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

is selected from the group consisting of:

In another aspect, the present invention provides compounds of Formula(I-1), (II-1), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

is selected from the group consisting of:

In another aspect, the present invention provides compounds of Formula(I-1), (II-1), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

In another aspect, the present invention provides compounds of Formula(I-1), (II-1), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), or (IIb), a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

R² is a 5-membered heterocycle substituted with 0-1 R^(2a), wherein saidheterocycle is selected from: pyrazolyl, imidazolyl, triazolyl, andtetrazolyl; and

R^(2a) is, independently at each occurrence, selected from the groupconsisting of: OH, NH₂, CH₂OH, CO₂H, C₁₋₄ alkyl, —CONH₂, —CONH(C₁₋₄alkyl), and —CON(C₁₋₄ alkyl)₂

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), or (IIb), a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

R² is selected from the group consisting of: triazolyl and tetrazolyl.

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, wherein:

L₁ is selected from the group consisting of: a bond, —CH₂CH₂—, —CH═CH—,—C(Me)=CH—, —C≡C—, and —CH₂NH—;

L is selected from the group consisting of: C₃₋₇ alkylene and C₄₋₇alkenylene; wherein said alkylene and alkenylene are optionallysubstituted with 1-2 R⁷; optionally one or two of the carbon atoms ofsaid alkylene and alkenylene may be replaced by O, NH, N(C₁₋₄ alkyl),CONH, or CON(C₁₋₄ alkyl);

Y is selected from the group consisting of: CH₂, CH(C₁₋₄ alkyl), C(C₁₋₄alkyl)₂, O, S, NH, N(C₁₋₄ alkyl), —CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄alkyl)CH₂—, —OCONH—, —NHCONH—, and —SO₂NH—;

R¹ is, independently at each occurrence, selected from: halogen, CN, OH,OCF₃, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), NH₂,—C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, and —SO₂NH₂;

R³ is selected from the group consisting of: H, halogen, OH, NH₂, CF₃,C₁₋₄ alkyl, C₁₋₄ alkoxy, —CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), —C(O)NH₂,—C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, and —CH₂CO₂H; and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂,—CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂,—NHSO₂(C₁₋₄ alkyl), —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), and—CONH₂.

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, wherein:

L₁ is selected from the group consisting of: a bond, —CH₂CH₂— and—CH═CH—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, CN, C₁₋₄ alkyl, CHF₂, CF₃, CO(C₁₋₄ alkyl), NH₂,—CH₂NH₂, and —C(═NH)NH₂;

R³ is selected from the group consisting of: H, halogen, CF₃, CO₂H,CO₂(C₁₋₄ alkyl), and C₁₋₄ alkyl; and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄ alkyl),—NHCO₂(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄ alkyl), and —CONH₂.

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, wherein:

L₁ is selected from the group consisting of: a bond, —CH₂CH₂— and—CH═CH—;

L is selected from the group consisting of: —CH₂—CH═CH—CH₂—,—CH₂—CH═CH—(CH₂)₂—, —CH₂—CH═CH—(CH₂)₃—, —CH₂—CH═C(C₁₋₄ alkyl)-(CH₂)₂—,—CH₂—CH═CH—CH(C₁₋₄ alkyl)-CH₂—, —CH₂—C(C₁₋₄ alkyl)=CH—(CH₂)₂—,—(CH₂)₃CH(C₁₋₄ alkyl)CH₂—, —(CH₂)₂CH(C₁₋₄ alkyl)(CH₂)₂—, —(CH₂)₃CH(C₁₋₄alkyl)(CH₂)₂—, —(CH₂)₃CH(C₁₋₄ alkyl)-, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—,—(CH₂)₆—, —CH₂O(CH₂)₃—, —CH₂O(CH₂)₄—, —(CH₂)₄CF₂—, —(CH₂)₄CH(CF₃)—,—CH₂—CH═CH—CH₂CF₂—, —CH₂NHCOCF₂CH₂—, —CH₂NH(CH₂)₂—, —CH₂NH(CH₂)₃—,—CH₂NH(CH₂)₄—, —(CH₂)₂NHCH₂—, —(CH₂)₂N(C₁₋₄ alkyl)CH₂—, —(CH₂)₂N(C₁₋₄alkyl)(CH₂)₂—, —CH₂—CONH—(CH₂)₂—, —CH₂—CONH—(CH₂)₃—, —CH₂—CONH—(CH₂)₄—,—CH₂—CON(C₁₋₄ alkyl)-(CH₂)₂—, —CH₂—CON(C₁₋₄ alkyl)-(CH₂)₃—,—CH₂CH(OH)(CH₂)₂—, —(CH₂)₂CH(OH)CH₂—, and —CH₂CH(OH)CH(OH)CH₂—;

Y is selected from the group consisting of: —CH₂—, O, NH, N(C₁₋₄ alkyl),—NHCO—, —CONH—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —NHCONH—, and—SO₂NH—;

R³ is selected from the group consisting of: H, C₁₋₄ alkyl, and halogen;and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, CO₂H, CO₂(C₁₋₄ alkyl), NH₂, NHCO₂(C₁₋₄ alkyl),and —CH₂NHCO₂(C₁₋₄ alkyl).

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, wherein:

L is selected from the group consisting of: —CH₂—CH═CH—CH₂—,—CH₂—CH═CH—(CH₂)₂—, —CH₂—CH═CH—(CH₂)₃—, —CH₂—CH═C(C₁₋₄ alkyl)-(CH₂)₂—,—CH₂—CH═CH—CH(C₁₋₄ alkyl)-CH₂—, —CH₂—C(C₁₋₄ alkyl)=CH—(CH₂)₂—,—(CH₂)₃CH(C₁₋₄ alkyl)CH₂—, —(CH₂)₃CH(C₁₋₄ alkyl)(CH₂)₂—, —(CH₂)₃CH(C₁₋₄alkyl)-, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CH₂O(CH₂)₃—,—CH₂O(CH₂)₄—, —(CH₂)₄CF₂—, —(CH₂)₄CH(CF₃)—, —CH₂—CH═CH—CH₂CF₂—,—CH₂NHCOCF₂CH₂—, —CH₂NH(CH₂)₂—, —CH₂NH(CH₂)₃—, —CH₂NH(CH₂)₄—,—(CH₂)₂NHCH₂—, —(CH₂)₂N(C₁₋₄ alkyl)CH₂—, —(CH₂)₂N(C₁₋₄ alkyl)(CH₂)₂—,—CH₂—CONH—(CH₂)₂—, —CH₂—CONH—(CH₂)₃—, —CH₂—CONH—(CH₂)₄—, —CH₂—CON(C₁₋₄alkyl)-(CH₂)₂—, —CH₂—CON(C₁₋₄ alkyl)-(CH₂)₃—, —CH₂CH(OH)(CH₂)₂—,—(CH₂)₂CH(OH)CH₂—, and —CH₂CH(OH)CH(OH)CH₂—;

Y is selected from the group consisting of: CH₂, O, NH, N(C₁₋₄ alkyl),—NHCO—, —CONH—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —NHCONH—, and—SO₂NH—;

R¹ is selected from the group consisting of: halogen, C₁₋₄ alkyl, CHF₂,CN, and CO(C₁₋₄ alkyl);

R³ is selected from the group consisting of: H, C₁₋₄ alkyl, and halogen;and

R⁶ is, independently at each occurrence, is selected from the groupconsisting of: halogen, NH₂, NHCO₂(C₁₋₄ alkyl), and —CH₂NHCO₂(C₁₋₄alkyl).

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, wherein:

L is selected from the group consisting of: —CH₂—CH═CH—CH₂—,—CH₂—CH═CH—(CH₂)₂—, —CH₂—CH═CH—(CH₂)₃—, —CH₂—CH═C(CH₃)—(CH₂)₂—,—CH₂—CH═CH—CH(CH₃)CH₂—, —(CH₂)₃CH(CH₃)CH₂—, —(CH₂)₂CH(CH₃)(CH₂)₂—,—(CH₂)₃CH(CH₃)—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CH₂O(CH₂)₃—,—CH₂O(CH₂)₄—, —(CH₂)₄CF₂—, —(CH₂)₄CH(CF₃)—, —CH₂—CH═CH—CH₂CF₂—,—CH₂NHCOCF₂CH₂—, —CH₂NH(CH₂)₂—, —CH₂NH(CH₂)₃—, —CH₂NH(CH₂)₄—,—(CH₂)₂NHCH₂—, —(CH₂)₂N(CH₃)CH₂—, —(CH₂)₂N(CH₃)(CH₂)₂—,—CH₂—CONH—(CH₂)₂—, —CH₂—CONH—(CH₂)₃—, —CH₂—CONH—(CH₂)₄—,—CH₂—CON(CH₃)—(CH₂)₂—, —CH₂—CON(CH₃)—(CH₂)₃—, —CH₂CH(OH)(CH₂)₂—,—(CH₂)₂CH(OH)CH₂—, and —CH₂CH(OH)CH(OH)CH₂—;

Y is selected from the group consisting of: CH₂, O, NH, NMe, —CONH—,—NHCO—, —CONHCH₂—, —CONMeCH₂—, —OCONH—, —NHCONH—, and —SO₂NH—;

R¹ is selected from the group consisting of: H, F, Cl, Me, COMe, andCHF₂;

R³ is selected from the group consisting of: H, Me, and Cl; and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: F, NH₂, NHCO₂Me, and —CH₂NHCO₂Me.

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, within the scope of any one of the above aspects,wherein:

L is selected from the group consisting of: —CH₂—CH═CH—CH₂—,—CH₂—CH═CH—(CH₂)₂—, —CH₂—CH═CH—(CH₂)₃—, —CH₂—CH═C(CH₃)—(CH₂)₂—,—CH₂—CH═CH—CH(CH₃)CH₂—, —(CH₂)₃CH(CH₃)CH₂—, —(CH₂)₂CH(CH₃)(CH₂)₂—,—(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CH₂O(CH₂)₃—, —CH₂O(CH₂)₄—, —(CH₂)₄CF₂—,—CH₂—CH═CH—CH₂CF₂—, —CH₂NH(CH₂)₂—, —CH₂NH(CH₂)₃—, —(CH₂)₂N(CH₃)CH₂—,—(CH₂)₂N(CH₃)(CH₂)₂—, —CH₂—CONH—(CH₂)₃—, —CH₂—CONH—(CH₂)₄—,—CH₂—CON(CH₃)—(CH₂)₂—, and —CH₂CH(OH)CH(OH)CH₂—;

Y is selected from the group consisting of: CH₂, O, NH, —CONH—, —NHCO—,—CONHCH₂—, —CONMeCH₂—, —OCONH—, —NHCONH—, and —SO₂NH—; and

R³ is selected from the group consisting of: H and Cl.

In another aspect, the present invention includes compounds of Formula(IIe) or (IIf) or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, a solvate, or a prodrug thereof, wherein:

is selected from the group consisting of:

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, wherein:

L is selected from the group consisting of: —CH₂—CH═CH—CH₂—,—CH₂—CH═CH—(CH₂)₂—, —CH₂—CH═CH—(CH₂)₃—, —CH₂—CH═C(CH₃)—(CH₂)₂—,—CH₂—CH═CH—CH(CH₃)CH₂—, —(CH₂)₃CH(CH₃)CH₂—, —(CH₂)₂CH(CH₃)(CH₂)₂—,—(CH₂)₃CH(CH₃)—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CH₂O(CH₂)₃—,—CH₂O(CH₂)₄—, —(CH₂)₄CF₂—, —(CH₂)₄CH(CF₃)—, —CH₂—CH═CH—CH₂CF₂—,—CH₂NHCOCF₂CH₂—, —CH₂NH(CH₂)₂—, —CH₂NH(CH₂)₃—, —CH₂NH(CH₂)₄—,—(CH₂)₂NHCH₂—, —(CH₂)₂N(CH₃)CH₂—, —(CH₂)₂N(CH₃)(CH₂)₂—,—CH₂—CONH—(CH₂)₂—, —CH₂—CONH—(CH₂)₃—, —CH₂—CONH—(CH₂)₄—,—CH₂—CON(CH₃)—(CH₂)₂—, —CH₂—CON(CH₃)—(CH₂)₃—, —CH₂CH(OH)(CH₂)₂—,—(CH₂)₂CH(OH)CH₂—, and —CH₂CH(OH)CH(OH)CH₂—;

Y is selected from the group consisting of: CH₂, O, NH, NMe, —CONH—,—NHCO—, —CONHCH₂—, —CONMeCH₂—, —OCONH—, —NHCONH—, and —SO₂NH—;

R¹ is selected from the group consisting of: H, F, Cl, Me, COMe, andCHF₂;

R³ is selected from the group consisting of: H, Me, and Cl; and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: F, NH₂, NHCO₂Me, and —CH₂NHCO₂Me.

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, wherein:

L is selected from the group consisting of: —CH₂—CH═CH—CH₂—,—CH₂—CH═CH—(CH₂)₂—, —CH₂—CH═CH—(CH₂)₃—, —CH₂—CH═C(CH₃)—(CH₂)₂—,—CH₂—CH═CH—CH(CH₃)CH₂—, —(CH₂)₃CH(CH₃)CH₂—, —(CH₂)₂CH(CH₃)(CH₂)₂—,—(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CH₂O(CH₂)₃—, —CH₂O(CH₂)₄—, —(CH₂)₄CF₂—,—CH₂—CH═CH—CH₂CF₂—, —CH₂NH(CH₂)₂—, —CH₂NH(CH₂)₃—, —(CH₂)₂N(CH₃)CH₂—,—(CH₂)₂N(CH₃)(CH₂)₂—, —CH₂—CONH—(CH₂)₃—, —CH₂—CONH—(CH₂)₄—,—CH₂—CON(CH₃)—(CH₂)₂—, and —CH₂CH(OH)CH(OH)CH₂—;

Y is selected from the group consisting of: CH₂, O, NH, —CONH—, —NHCO—,—CONHCH₂—, —CONMeCH₂—, —OCONH—, —NHCONH—, and —SO₂NH—; and

R³ is selected from the group consisting of: H and Cl.

In another aspect, the present invention includes compounds of Formula(IIe) or (IIf) or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, a solvate, or a prodrug thereof, wherein:

is selected from the group consisting of:

In another aspect, the present invention includes compounds of Formula(III):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, wherein:

L is selected from the group consisting of: —CH₂—CH═CH—CH₂—,—CH₂—CH═CH—(CH₂)₂—, —CH₂—CH═CH—(CH₂)₃—, —CH₂—CH═C(CH₃)—(CH₂)₂—,—CH₂—CH═CH—CH(CH₃)CH₂—, —(CH₂)₃CH(CH₃)CH₂—, —(CH₂)₂CH(CH₃)(CH₂)₂—,—(CH₂)₃CH(CH₃)—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CH₂O(CH₂)₃—,—CH₂O(CH₂)₄—, —(CH₂)₄CF₂—, —(CH₂)₄CH(CF₃)—, —CH₂—CH═CH—CH₂CF₂—,—CH₂NHCOCF₂CH₂—, —CH₂NH(CH₂)₂—, —CH₂NH(CH₂)₃—, —CH₂NH(CH₂)₄—,—(CH₂)₂NHCH₂—, —(CH₂)₂N(CH₃)CH₂—, —(CH₂)₂N(CH₃)(CH₂)₂—,—CH₂—CONH—(CH₂)₂—, —CH₂—CONH—(CH₂)₃—, —CH₂—CONH—(CH₂)₄—,—CH₂—CON(CH₃)—(CH₂)₂—, —CH₂—CON(CH₃)—(CH₂)₃—, —CH₂CH(OH)(CH₂)₂—,—(CH₂)₂CH(OH)CH₂—, and —CH₂CH(OH)CH(OH)CH₂—;

Y is selected from the group consisting of: CH₂, O, NH, NMe, —CONH—,—NHCO—, —CONHCH₂—, —CONMeCH₂—, —OCONH—, —NHCONH—, and —SO₂NH—;

R^(1b) is selected from the group consisting of: H and F;

R³ is selected from the group consisting of: H, Me, and Cl; and

R^(6a) is selected from the group consisting of: H, F, NH₂, and NHCO₂Me.

In another aspect, the present invention includes compounds of Formula(III), or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, a solvate, or a prodrug thereof, wherein:

L is selected from the group consisting of: —CH₂—CH═CH—CH₂—,—CH₂—CH═CH—(CH₂)₂—, —CH₂—CH═CH—(CH₂)₃—, —CH₂—CH═C(CH₃)—(CH₂)₂—,—CH₂—CH═CH—CH(CH₃)CH₂—, —(CH₂)₃CH(CH₃)CH₂—, —(CH₂)₂CH(CH₃)(CH₂)₂—,—(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CH₂O(CH₂)₃—, —CH₂O(CH₂)₄—, —(CH₂)₄CF₂—,—CH₂—CH═CH—CH₂CF₂—, —CH₂NH(CH₂)₂—, —CH₂NH(CH₂)₃—, —(CH₂)₂N(CH₃)CH₂—,—(CH₂)₂N(CH₃)(CH₂)₂—, —CH₂—CONH—(CH₂)₃—, —CH₂—CONH—(CH₂)₄—,—CH₂—CON(CH₃)—(CH₂)₂—, and —CH₂CH(OH)CH(OH)CH₂—;

Y is selected from the group consisting of: CH₂, O, NH, —CONH—, —NHCO—,—CONHCH₂—, —CONMeCH₂—, —OCONH—, —NHCONH—, and —SO₂NH—;

R^(1b) is selected from the group consisting of: H and F;

R³ is selected from the group consisting of: H and Cl; and

R^(6a) is selected from the group consisting of: H, F, NH₂, and NHCO₂Me.

In another aspect, the present invention includes compounds of Formula(III), or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, a solvate, or a prodrug thereof, wherein:

L is selected from the group consisting of: —CH₂—CH═CH—CH₂—,—CH₂—CH═CH—(CH₂)₂—, —CH₂—CH═CH—(CH₂)₃—, —CH₂—CH═C(CH₃)—(CH₂)₂—,—CH₂—CH═CH—CH(CH₃)CH₂—, —(CH₂)₃CH(CH₃)—, —(CH₂)₃CH(CH₃)CH₂—,—(CH₂)₂CH(CH₃)(CH₂)₂—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CH₂O(CH₂)₃—,—CH₂O(CH₂)₄—, —(CH₂)₄CF₂—, —(CH₂)₄CH(CF₃)—, —CH₂—CH═CH—CH₂CF₂—,—CH₂NH(CH₂)₂—, —CH₂NH(CH₂)₃—, —CH₂NH(CH₂)₄—, —(CH₂)₂N(CH₃)CH₂—,—(CH₂)₂N(CH₃)(CH₂)₂—, —CH₂CH(OH)(CH₂)₂—, —(CH₂)₂CH(OH)CH₂—, and—CH₂CH(OH)CH(OH)CH₂—;

Y is selected from the group consisting of: CH₂, O, NH, —CONH—, —NHCO—,—OCONH—, —NHCONH—, —CONHCH₂—, and —SO₂NH—; and

R³ is selected from the group consisting of: H and Cl.

In another aspect, the present invention includes compounds of Formula(IV):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, within the scope of any one of the aboveaspects, wherein:

is selected from the group consisting of:

L is selected from the group consisting of: —CH₂—CH═CH—CH₂—,—CH₂—CH═CH—(CH₂)₂—, —(CH₂)₄—, and —(CH₂)₅—;

Y is —CONH—;

R³ is selected from the group consisting of: H and Cl; and

R^(6a) is selected from the group consisting of: H, F, —NHCO₂Me, and—CH₂NHCO₂Me.

In another aspect, the present invention includes compounds of Formula(V): or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,a solvate, or a prodrug thereof, wherein:

ring B is selected from the group consisting of:

L is selected from the group consisting of: —CH₂—CH═CH—(CH₂)₂—,—CH₂—CH═CH—CH₂CF₂—, and —(CH₂)₄—;

Y is selected from the group consisting of: CH₂ and —CONH—;

R³ is selected from the group consisting of: H and Cl; and

R^(6a) is selected from the group consisting of: H and —NHCO₂Me.

In another embodiment, the compounds of the present invention haveFactor XIa Ki values ≤10 μM.

In another embodiment, the compounds of the present invention haveFactor XIa Ki values ≤1 μM.

In another embodiment, the compounds of the present invention haveFactor XIa Ki values ≤0.5 μM.

In another embodiment, the compounds of the present invention haveFactor XIa Ki values ≤0.1 μM. ps II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate, thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s). In apreferred embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof. Preferably, theanti-platelet agent(s) are clopidogrel and/or aspirin, or a combinationthereof.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of a thromboembolic disorder comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a compound of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, for use in therapy for thetreatment and/or prophylaxis of a thromboembolic disorder.

In another embodiment, the present invention also provides the use of acompound of the present invention or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof, for themanufacture of a medicament for the treatment and/or prophylaxis of athromboembolic disorder.

In another embodiment, the present invention provides a method fortreatment and/or prophylaxis of a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a first and second therapeutic agent, wherein the firsttherapeutic agent is a compound of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, and the second therapeutic agent is at least one agentselected from a second Factor Xa inhibitor, an anti-coagulant agent, ananti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent,and a fibrinolytic agent. Preferably, the second therapeutic agent is atleast one agent selected from warfarin, unfractionated heparin, lowmolecular weight heparin, synthetic pentasaccharide, hirudin,argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin,mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam,ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab,melagatran, desulfatohirudin, tissue plasminogen activator, modifiedtissue plasminogen activator, anistreplase, urokinase, andstreptokinase. Preferably, the second therapeutic agent is at least oneanti-platelet agent. Preferably, the anti-platelet agent(s) areclopidogrel and/or aspirin, or a combination thereof.

The thromboembolic disorder includes arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, arterial cerebrovascular thromboembolic disorders, and venouscerebrovascular thromboembolic disorders. Examples of the thromboembolicdisorder include, but are not limited to, unstable angina, an acutecoronary syndrome, atrial fibrillation, first myocardial infarction,recurrent myocardial infarction, ischemic sudden death, transientischemic attack, stroke, atherosclerosis, peripheral occlusive arterialdisease, venous thrombosis, deep vein thrombosis, thrombophlebitis,arterial embolism, coronary arterial thrombosis, cerebral arterialthrombosis, cerebral embolism, kidney embolism, pulmonary embolism, andthrombosis resulting from medical implants, devices, or procedures inwhich blood is exposed to an artificial surface that promotesthrombosis.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of an inflammatory disorder comprising:administering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof. Examples of the inflammatorydisorder include, but are not limited to, sepsis, acute respiratorydistress syndrome, and systemic inflammatory response syndrome.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intreatment and/or prophylaxis of a thromboembolic disorder.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

The term “stereoisomer” refers to isomers of identical constitution thatdiffer in the arrangement of their atoms in space. Enantiomers anddiastereomers are examples of stereoisomers. The term “enantiomer”refers to one of a pair of molecular species that are mirror images ofeach other and are not superimposable. The term “diastereomer” refers tostereoisomers that are not mirror images. The term “racemate” or“racemic mixture” refers to a composition composed of equimolarquantities of two enantiomeric species, wherein the composition isdevoid of optical activity.

The symbols “R” and “S” represent the configuration of substituentsaround a chiral carbon atom(s). The isomeric descriptors “R” and “S” areused as described herein for indicating atom configuration(s) relativeto a core molecule and are intended to be used as defined in theliterature (IUPAC Recommendations 1996, Pure and Applied Chemistry,68:2193-2222 (1996)).

The term “chiral” refers to the structural characteristic of a moleculethat makes it impossible to superimpose it on its mirror image. The term“homochiral” refers to a state of enantiomeric purity. The term “opticalactivity” refers to the degree to which a homochiral molecule ornonracemic mixture of chiral molecules rotates a plane of polarizedlight.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁ to C₁₀alkyl” or “C₁₋₁₀ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Additionally, forexample, “C₁ to C₆ alkyl” or “C₁-C₆ alkyl” denotes alkyl having 1 to 6carbon atoms. Alkyl group can be unsubstituted or substituted with atleast one hydrogen being replaced by another chemical group. Examplealkyl groups include, but are not limited to, methyl (Me), ethyl (Et),propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl,t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When “C₀alkyl” or “C₀ alkylene” is used, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. “C₁ to C₆alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxy groups include, but arenot limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), and t-butoxy. Similarly, “alkylthio” or “thioalkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through a sulphur bridge; for example methyl-S—and ethyl-S—.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁ to C₆ haloalkoxy” or “C₁₋₆ haloalkoxy”,is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups.Examples of haloalkoxy include, but are not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.Similarly, “haloalkylthio” or “thiohaloalkoxy” represents a haloalkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example trifluoromethyl-S—, andpentafluoroethyl-S—.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. “C₃ to C₇ cycloalkyl” or “C₃₋₇cycloalkyl” is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.Branched cycloalkyl groups such as 1-methylcyclopropyl and2-methylcyclopropyl are included in the definition of “cycloalkyl”.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclicor 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring,any of which may be saturated, partially unsaturated, unsaturated oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridgedrings are also included in the definition of carbocycle (e.g.,[2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,and indanyl. When the term “carbocycle” is used, it is intended toinclude “aryl”. A bridged ring occurs when one or more carbon atoms linktwo non-adjacent carbon atoms. Preferred bridges are one or two carbonatoms. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, and phenanthranyl. Arylmoieties are well known and described, for example, in Hawley'sCondensed Chemical Dictionary (13th Edition), Lewis, R. J., ed., J.Wiley & Sons, Inc., New York (1997). “C₆ or C₁₀ aryl” or “C₆₋₁₀ aryl”refers to phenyl and naphthyl. Unless otherwise specified, “aryl”, “C₆or C₁₀ aryl” or “C₆₋₁₀ aryl” or “aromatic residue” may be unsubstitutedor substituted with 1 to 5 groups, preferably 1 to 3 groups, OH, OCH₃,Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃, SCH₃,S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, and CO₂CH₃.

The term “benzyl,” as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic orbicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclicheterocyclic ring that is saturated, partially unsaturated, or fullyunsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S; and

including any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more atoms (i.e., C, O, N, or S) linktwo non-adjacent carbon or nitrogen atoms. Examples of bridged ringsinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge.

The term “counterion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbonyl group or double bond be part (i.e., within) of thering. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R groups, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two;

generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 18th Edition, MackPublishing Company, Easton, Pa. (1990), the disclosure of which ishereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

a) Design of Prodrugs, Bundgaard, H., ed., Elsevier (1985), and Methodsin Enzymology, 112:309-396, Widder, K. et al., eds., Academic Press(1985);

b) Bundgaard, H., Chapter 5: “Design and Application of Prodrugs,” ATextbook of Drug Design and Development, pp. 113-191, Krosgaard-Larsen,P. et al., eds., Harwood Academic Publishers (1991);

c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);

d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and

e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, Medicinal Chemistry: Principles and Practice, King, F. D., ed.The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry andEnzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); The Practiceof Medicinal Chemistry, Wermuth, C. G., ed., Academic Press, San Diego,Calif. (1999).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds have a variety of potential uses,e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrate, “sat” or “sat'd” for saturated, “MW” for molecular weight,“mp” for melting point, “ee” for enantiomeric excess, “MS” or “MassSpec” for mass spectrometry, “ESI” for electrospray ionization massspectroscopy, “HR” for high resolution, “HRMS” for high resolution massspectrometry, “LCMS” for liquid chromatography mass spectrometry, “HPLC”for high pressure liquid chromatography, “RP HPLC” for reverse phaseHPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” for nuclearmagnetic resonance spectroscopy, “nOe” for nuclear Overhauser effectspectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, and “Z” arestereochemical designations familiar to one skilled in the art.

-   Me methyl-   Et ethyl-   Pr propyl-   i-Pr isopropyl-   Bu butyl-   i-Bu isobutyl-   t-Bu tert-butyl-   Ph phenyl-   Bn benzyl-   Boc tert-butyloxycarbonyl-   AcOH or HOAc acetic acid-   AlCl₃ aluminum chloride-   AIBN azobisisobutyronitrile-   BBr₃ boron tribromide-   BCl₃ boron trichloride-   BEMP    2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Burgess reagent 1-methoxy-N-triethylammoniosulfonyl-methanimidate-   CBz carbobenzyloxy-   CH₂Cl₂ dichloromethane-   CH₃CN or ACN acetonitrile-   CDCl₃ deutero-chloroform-   CDCl₃ chloroform-   mCPBA or m-meta-chloroperbenzoic acid-   CPBA-   Cs₂CO₃ cesium carbonate-   Cu(OAc)₂ copper (II) acetate-   Cy₂NMe N-cyclohexyl-N-methylcyclohexanamine-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCE 1,2 dichloroethane-   DCM dichloromethane-   DEA diethylamine-   Dess-Martin    1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-beniziodoxol-3-(1H)-one-   DIC or DIPCDI diisopropylcarbodiimide-   DIEA, DIPEA or diisopropylethylamine-   Hunig's base-   DMAP 4-dimethylaminopyridine-   DME 1,2-dimethoxyethane-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   cDNA complimentary DNA-   Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane-   DuPhos (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene-   EDC N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide-   EDCI N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   (S,S)-(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5--   EtDuPhosRh(I) cyclooctadiene)rhodium(I) trifluoromethanesulfonate-   Et₃N or TEA triethylamine-   EtOAc ethyl acetate-   Et₂O diethyl ether-   EtOH ethanol-   GMF glass microfiber filter-   Grubbs (II)    (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)    (triycyclohexylphosphine)ruthenium-   HCl hydrochloric acid-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES 4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid-   Hex hexane-   HOBt or HOBT 1-hydroxybenzotriazole-   H₂SO₄ sulfuric acid-   K₂CO₃ potassium carbonate-   KOAc potassium acetate-   K₃PO₄ potassium phosphate-   LAH lithium aluminum hydride-   LG leaving group-   LiOH lithium hydroxide-   MeOH methanol-   MgSO₄ magnesium sulfate-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   Na₂CO₃ sodium carbonate-   NaOH sodium hydroxide-   Na₂SO₃ sodium sulfite-   Na₂SO₄ sodium sulfate-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NH₃ ammonia-   NH₄Cl ammonium chloride-   NH₄OH ammonium hydroxide-   OTf triflate or trifluoromethanesulfonate-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   Pd(OAc)₂ palladium(II) acetate-   Pd/C palladium on carbon-   Pd(dppf)Cl₂    [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-   Ph₃PCl₂ triphenylphosphine dichloride-   PG protecting group-   PL-HCO₃ MP SPE Solid phase anion exchange-   POCl₃ phosphorus oxychloride-   i-PrOH or IPA isopropanol-   PS polystyrene-   SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride-   SiO₂ silica oxide-   SnCl₂ tin(II) chloride-   TBAI tetra-n-butylammonium iodide-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TMSCHN₂ trimethylsilyldiazomethane-   T3P propane phosphonic acid anhydride-   TRIS tris(hydroxymethyl)aminomethane

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al. (Protective Groups in Organic Synthesis,4th Edition, Wiley-Interscience (2006)).

Imidazole derivatives useful for the synthesis of the compounds of thisinvention may be synthesized according to the general method outlined inScheme 1 (Contour-Galcera et al., Bioorg. Med. Chem. Lett.,11(5):741-745 (2001)). Alkylation of the potassium or cesium carboxylateof an appropriately protected or derivatized alpha amino acid 1a with asuitably substituted alpha-bromoketone 1b (ring C is aryl or heteroaryl)provides the keto ester 1c. The imidazole 1 d is formed by heating theketo ester 1c to reflux in a suitable solvent, such as toluene orxylenes, in the presence of excess ammonium acetate using a Dean-Starktrap to remove water. Formation of the imidazole can also be carried outby combining the keto ester 1c and ammonium acetate in a suitablesolvent, such as xylene or ethanol or a combination of solvents such asdimethylformamide and ethanol (1:1) and using microwave heating.Imidazole 1d can then be protected with as suitable protecting group.For example, imidazole 1d can be reacted with SEM-Cl, in the presence ofbase, such as sodium hydride or dicyclohexylmethyl amine, and in asolvent such as dimethylformamide or tetrahydrofuran to give 1e.

Imidazole containing macrocycles of this invention wherein Y is —CH₂—can be prepared according to Scheme 2. Suzuki-Miyaura coupling between2a, prepared as described in Scheme 1, and a suitably substituted alkylboronic acid 2b in the presence of silver(I) oxide and a base, such aspotassium carbonate, using a precatalyst such as Pd(dppf)Cl₂.CH₂Cl₂complex, in a solvent such as tetrahydrofuran at elevated temperaturesprovides 2c (Falck, J. R., Tetrahedron Letters, 42:7213 (2001)). Using amodified procedure described by Lovely (Tetrahedron Letters, 44:1379(2003)), 2c, following pretreatment with p-toluenesulfonic acid to formthe imidazolium ion, can be cyclized via ring-closing metathesis using acatalyst, such as Grubbs (II), in a suitable solvent, such asdichloromethane, dichloroethane, or toluene at elevated temperature, togive the imidazole-containing macrocycle as a mixture of olefin isomers(E-alkene 2d and Z-alkene 2e). The olefins can be separated, and thendeprotection of both the Boc and SEM groups with aqueous 5M hydrochloricacid in methanol or ethanol at elevated temperature provides amines 2fand 2g. Alternatively, the deprotection can be performed under anhydrousconditions with 4M hydrochloric acid in dioxane at elevatedtemperatures. The mixture of olefin isomers (E-alkene 2d and Z-alkene2e) can be reduced with hydrogen over either palladium on carbon orplatinum oxide and subsequent deprotection as described above gives thesaturated amine 2h. Amide coupling between amines 2f-h, with anappropriately substituted carboxylic acid 2k, employing suitablecoupling reagents, such as EDCI, HOBt, and base generates 2m-o (foralternative coupling reagents see: Han, S.-Y. et al., Tetrahedron,60:2447 (2004)). Alternately, amines 2f-h can be coupled with anactivated carboxylic ester 21 in the presence of a base such as Hunig'sbase and in a solvent such as dimethylformamide to give 2m-o. Furtherfunctional group incorporation on the imidazole ring may be achieved bychlorination of the C-5 of the imidazole ring with N-chlorosuccinimide,using a suitable solvent such as methylene chloride, acetonitrile orchloroform to give compounds 2p-r. Further functional groupincorporation on the imidazole ring may also be achieved by fluorinationof the C-5 of the imidazole ring with Accufluor, using a suitablesolvent such as dimethylformamide in the presence of a base, such assodium carbonate.

Imidazole containing macrocycles of this invention wherein Y is NH,NHC(O), NHCO₂, NHC(O)NH, and NHSO₂ can be prepared according to Scheme3. Using a modified procedure described by Ma (Synthesis, 3:496 (2005)),bromide 2a can be coupled with an appropriately substituted amine 3aemploying copper (I) iodide and L-proline in the presence of a base suchas potassium carbonate, in a solvent such as dimethylsulfoxide atelevated temperature to give the substituted aniline 3g. Alternatively,bromide 2a can be converted to the unsubstituted aniline 3b undersimilar reaction conditions (Chang, S., Chem. Commun., 3052 (2008)). Theaniline 3b can then be coupled with an appropriately substitutedcarboxylic acid 3c using T3P in a solvent such as ethyl acetate ordimethylformamide to give the amide 3h. The aniline 3b can also becoupled with an appropriately substituted chloroformate 3d, isocyanate3e, or sulfonyl chloride 3f to provide the carbamate 3k, urea 3l, andthe sulfonamide 3m, respectively. Compounds of the formula 3g, 3h, and3k-m can be converted to compounds 3n-r according to Scheme 2. For thepreparation of compounds of the formulae 3n, the preferred method forremoving both the Boc and SEM, as described in Scheme 2, employsanhydrous 4M hydrochloric acid in dioxane at elevated temperatures witheither cysteine or O-methyl hydroxylamine as a formaldehyde scavenger.

Imidazole-containing macrocycles of this invention wherein Y is C(O)NHcan be prepared according to Scheme 4. Subjecting 2a to methyllithiumfollowed by metal-halogen exchange with n-butyllithium and quenching theintermediate anion with carbon dioxide provides the carboxylic acid 4a.Amide coupling with an appropriately substituted amine 4b, as previouslydescribed for the conversion of 3b to 3h, gives amide 4c. Amide 4c canbe converted to compounds 4d-f according to Scheme 2.

Certain 2-bromoacetophenone analogs (1b, C=aryl) that are notcommercially available may be synthesized from commercially availablestarting materials as described in Scheme 6. Acetophenone derivatives 6acan be treated with a brominating reagent such as bromine in a solventsuch chloroform to give 6b. Alternatively, acetophenone derivatives 6acan be treated with either copper (II) bromide in a solvent such asethyl acetate at elevated temperature or phenyltrimethylammoniumtribromide in a solvent such as tetrahydrofuran at low temperature toprovide 6b. Benzoic acid derivatives 6c can be treated sequentially withoxalyl chloride in a suitable solvent, such as dichloromethane,containing a few drops of DMF, and then treated withtrimethylsilyldiazomethane in a suitable solvent or solvent combination,such as acetonitrile and hexane. The intermediate diazoketone isisolated and treated with aqueous hydrobromic acid and dichloromethaneto provide 6b. Alternatively the benzoic acid derivatives 6c can beconverted to the acetophenone derivatives 6a in three steps as describedin Scheme 6. Alternatively, Stille coupling between a suitablysubstituted aryl halide or triflate and tributyl-(1-ethoxyvinyl)stannane with a palladium catalyst, such asbis-(triphenylphosphine)palladium dichloride, in a suitable solvent,such as toluene, at elevated temperature yields the enol ether 6e. Theresulting enol ether 6e can be converted to 6b with N-bromosuccinimide.

The syntheses of appropriately substituted carboxylic acids of formulae2k, where A=aryl and where L₁=—CH₂CH₂—, —CH═CH—, —C≡C—, —OCH₂—,—S(O)_(p)CH₂—, or —CH₂NH—, useful for the synthesis of amide compoundsof this invention as outlined in Scheme 2 are described in PCTInternational Application No. WO 2009/114677 published Sep. 17, 2009,which is incorporated in its entirety herein by reference. In addition,1-amino-5,6,7,8-tetrahydroisoquinoline-6-carboxylic acid useful for thesynthesis of amide compounds of this invention as outlined in Scheme 2is described in U.S. Patent Application No. 2005/0282805 published Dec.22, 2005, which is incorporated in its entirety herein by reference.

Representative pyridine (ring B=pyridine) containing macrocycles of thisinvention wherein Y is NHCO can be prepared as shown in Scheme 7.Condensation of aldehyde 7a, prepared according to a modified proceduredescribed by Negi (Synthesis, 991 (1996)), with(S)-2-methylpropane-2-sulfinamide in the presence of anhydrous coppersulfate in a solvent such as dichloromethane gives the sulfinimine 7b(Ellman, J., J. Org. Chem., 64:1278 (1999).) Using a modified proceduredescribed by Kuduk (Tetrahedron Letters, 45:6641 (2004)), suitablysubstituted Grignard reagents, for example allylmagnesium bromide, canbe added to sulfinimine 7b to give a sulfinamide 7c, as a mixture ofdiastereomers which can be separated at various stages of the sequence.Suzuki-Miyaura coupling between 4-chloropyridine 7c and an appropriatelysubstituted aryl or heteroaryl boronic acid or ester 7d in the presenceof a base such as potassium phosphate in a solvent mixture, suchdimethylsulfoxide and water, or dimethylformamide, using a precatalystsuch as Pd(dppf)Cl₂.CH₂Cl₂ complex provides 7e. Protecting groupinterconversion can be accomplished in two steps to give 7f. The aniline7f can then be coupled with an appropriately substituted carboxylic acid3c using propane phosphonic acid anhydride (T3P) to give the amide 7g.Ring closing metathesis, as described previously in Scheme 2, affordsthe pyridine containing macrocycle 7h, as the E-alkene. Boc deprotectionon 7h with either TFA in dichloromethane or 4M hydrochloric acid indioxane gives amine 7k. Alternatively, hydrogenation of 7h followed byBoc deprotection with TFA in dichloromethane provides amine 7l.Compounds 7k and 7l can be converted to compounds 3m and 3n according toScheme 2.

Additional pyridine (ring B=pyridine) containing macrocycles of thisinvention wherein Y is NHCO₂, NHC(O)NH, and NHSO₂ can be preparedaccording to Scheme 7 by replacing 3c with an appropriately substitutedchloroformate 3d, isocyanate 3e, or sulfonyl chloride 3f. Additionalmacrocycles containing regioisomeric pyridine scaffolds to the onedescribed in Scheme 7 can be prepared by an analogous sequence.

Methods for synthesis of a large variety of substituted pyridinecompounds useful as starting materials for the preparation of compoundsof the present invention are well known in the art and have beenextensively reviewed. (For examples of methods useful for thepreparation of pyridine starting materials see: Kroehnke, F., Synthesis,1 (1976); “Pyridine and Its Derivatives”, The Chemistry of HeterocyclicCompounds, 14(Suppl. I-4), Abramovitch, R. A., ed., John Wiley & Sons,New York (1974); Comprehensive Heterocyclic Chemistry, 2:165-524,Boulton, A. J. et al., eds., Pergamon Press, New York (1984);Comprehensive Heterocyclic Chemistry, 5:1-300, McKillop, A., ed.,Pergamon Press, New York (1996)).

In cases where suitably substituted boronic acids are not commerciallyavailable, a modification to this approach may be adopted wherein anaryl halide is subjected to a palladium mediated coupling with a diboronspecies such as bis(pinacolato) diboron or bis(neopentylglycolato)diboron to provide the corresponding4,4,5,5-tetramethyl-[1,3,2]dioxaborolane or the5,5-dimethyl-[1,3,2]dioxaborolane intermediates using the method ofIshiyama, T. et al. (J. Org. Chem., 60(23):7508-7510 (1995)).Alternately, this same intermediate can be prepared by reaction of theintermediate halide with the corresponding dialkoxyhydroborane asdescribed by Murata et al. (J. Org. Chem., 62(19):6458-6459 (1997)). Theboron pinacolate intermediates can be used in place of boronic acids forcoupling to the aryl/heteroaryl halides or triflates or the boronpinacolate intermediate can be converted to the boronic acids.Alternately, the corresponding boronic acids can be prepared bymetal-halogen exchange of the aryl/heteroaryl halide, quenching with atrialkoxyborate reagent, and aqueous workup to provide the boronic acids(Miyaura, N. et al., Chem. Rev., 95:2457 (1995)).

It is also realized that the scope of intermediate synthesis can befurther extended outside the use of Suzuki-Miyaura coupling methodologysince the precursor aryl halides or triflates described above are alsoprecursors for Stille, Negishi, Hiyama, and Kumada-type cross couplingmethodologies (Tsuji, J., Transition Metal Reagents and Catalysts:Innovations in Organic Synthesis, John Wiley & Sons (2000); Tsuji, J.,Palladium Reagents and Catalysts: Innovations in Organic Synthesis, JohnWiley & Sons (1996).)

Representative phenyl (ring B=phenyl) containing macrocycles of thisinvention wherein Y is NHCO can be prepared as shown in Scheme 8. Usinga modification of the procedure described by Hart (J. Org. Chem.,48(3):289-294 (1983)), in situ generation of N-trimethylsilylaldiminesfrom a suitably substituted benzaldehyde 8a and lithiumbis(trimethylsilyl)amide, followed by the addition of Grignard oralkyllithium reagents 8b, for instance allylmagnesium bromide, givesafter aqueous work up the amine 8c. The amine can be protected as theBoc. Compounds of the formula 8e and 8f can be prepared following thesequence described in Scheme 7, by replacing 7c with 8d.

Representative pyridazine (ring B=pyridazine) containing macrocycles ofthis invention wherein Y is NHCO can be prepared as shown in Scheme 9.Using a modification of the Minisci reaction described by Cowden (Org.Lett., 5:4497-4499 (2003)), an appropriately protected or derivatizedalpha amino acid 1a and 3,6-dichloropyridazine 9a can be coupled atelevated temperature in the presence of silver nitrate, ammoniumpersulfate, and an acid, such as trifluoroacetic acid, in a solvent,such as water or a water/dimethylformamide mixture, to give compounds ofthe formulae 9b. Compound 9b wherein R═H, prepared using anappropriately protected glycine derivative of 1a, can be furtherfunctionalized by deprotonation with sec-BuLi and subsequent alkylationwith an appropriately substituted alkyl halide, for instance allylbromide, to give compound 9c. Suzuki-Miyaura coupling betweenchloropyridazine 9c and an appropriately substituted aryl or heteroarylboronic acid or ester 7d in the presence of a base such as potassiumphosphate in a solvent mixture, such dimethylsulfoxide and water, ordimethylformamide, using a precatalyst such as Pd(dppf)Cl₂.CH₂Cl₂complex provides 9d. Compounds of the formula 9e and 9f can be preparedfollowing the sequence described in Scheme 7, by replacing 7f with 9d.

Methods for the synthesis of a large variety of substituted pyridazinesuseful for the preparation of compounds of the present invention arewell known in the art. (For examples of methods useful for thepreparation of pyridazine starting materials see: “Pyridazines”, TheChemistry of Heterocyclic Compounds, Vol. 28, Castle, R. N., ed., JohnWiley & Sons, New York (1973); “The Pyridazines”, The Chemistry ofHeterocyclic Compounds, 57(Suppl. 1), Brown, D. J., ed., John Wiley &Sons, New York (2000); Comprehensive Heterocyclic Chemistry II, 6:1-93,Boulton, A. J., ed., Elsevier Science Inc., New York (1996)).

Oxadiazole derivatives useful for the synthesis of the compounds of thisinvention may be synthesized according to the general method outlined inScheme 10. A suitably protected amino acid 1a is coupled to a hydrazideof formula 10a in the presence of a coupling reagent such as HATU or T3Pto provide acylhydrazide 10b which is cyclized to the correspondingoxadiazole 10c by heating in the presence of Burgess reagent in asuitable solvent such as THF.

Representative oxadiazole (ring B=oxadiazole) containing macrocycles ofthis invention wherein Y is NHCO can be prepared as shown in Scheme 10a.Thus from N-Boc-allylglycine and a suitably substituted2-nitrophenylhydrazine, compounds of formula 10d can be obtained andthen converted into macrocyclic compounds of this invention usingsimilar chemistry to that described above in Scheme 7.

It should be recognized to one skilled in the art of organic synthesisthat additional macrocyclic compounds of this invention can be preparedby alternative cyclization strategies which are not limited to thering-closing metathesis strategy described in Scheme 2. For instance,macrolactamization can also be used as described in Scheme 11. Slowaddition of a solution 11a and Hunig's base in DMF to a solution BOPreagent in a mixture dichloromethane and DMF, provides macrocycle 11b.Hydrogenolysis of the Cbz provides the amine 11c. Amide coupling of theamine 11c with 2k or 21, as described in Scheme 2, and globaldeprotection gives 11d.

Additional imidazole containing macrocycles of this invention wherein Yis NH can be prepared according to Scheme 14. Using a modified proceduredescribed by Ma (Synthesis, 3:496 (2005)), bromide 2a can be coupledwith an appropriately substituted amine or amino acid (R⁷═CO₂H) 14aemploying copper (I) iodide and L-proline in the presence of a base suchas potassium carbonate, in a solvent such as dimethylsulfoxide atelevated temperature, followed by alkylation of the carboxylic acidmoiety with an alkyl iodide such as methyl iodide, gives the substitutedaniline 14b. Alternatively, 14b can be prepared using a modifiedprocedure described by Zhao (Synthesis, 19:3189 (2006)). Combininganiline 3b with appropriately substituted aldehdydes 14c in the presenceof maleic acid and allyltributyltin provides 14b. Alternatively, aniline3b can be condensed with trifluoroacealdehyde ethyl hemiacetal followedby the addition of Grignard reagents, such as allylmagnesium bromide,which gives 14d. Compounds of the formula 14b and 14d can be convertedto compounds 14e and 14f according to Scheme 2. For the preparation ofcompounds of the formulae 14e and 14f, the preferred method for removingboth the Boc and SEM, as described in Scheme 2, employs anhydrous 4Mhydrochloric acid in dioxane at elevated temperatures with eithercysteine or O-methyl hydroxylamine as a formaldehyde scavenger. Furthermanipulation of functional groups on R⁷ using methods known to oneskilled in the art of organic synthesis will give additional compoundsof the invention.

Additional imidazole macrocycles of this invention wherein R³ is CN, canbe prepared according to Scheme 15. Deprotection of intermediates 15gand 15h followed by amide coupling as described above will then provideadditional compounds of this invention. Further manipulation offunctional groups at R⁷ and R³ using methods known to one skilled in theart of organic synthesis and as exemplified in the specific examplesgiven below will give additional compounds of the invention.

Additional imidazole containing macrocycles of this invention can beprepared according to Scheme 16. Regioselective protection of the2,4-dibromo imidazole with SEM-Cl provides 16b. Metal-halogen exchangeof 16b with n-BuLi followed by quenching with dimethylformamide affordsa mixture of the C2 and C4 aldehydes. Condensation of the C2-aldehydewith (S)-2-methylpropane-2-sulfinamide in the presence of anhydrouscopper sulfate in a solvent such as dichloromethane gives thesulfinimine 16c. Appropriately substituted Grignard reagents, forexample allylmagnesium bromide, can be added to sulfinimine 16c to givesulfinamine 16d, as a mixture of diastereomers which can be separated atvarious stages of the sequence. Alternatively, the 2, 4, 5-tribromoimidazole 16e can be converted to 16h according to the four stepsequence described above. Regioselective halogen-magnesium exchange of16h with isopropylmagnesium chloride, followed by quenching withsaturated ammonium chloride, provides 16d. Suzuki-Miyaura couplingbetween bromoimidazole 16d and an appropriately substituted aryl orheteroaryl boronic acid or ester 7d in the presence of a base such aspotassium carbonate in a solvent, such dioxane, using a catalyst such asPd(tBu₃P)₂ provides 16k. Protecting group interconversion can beaccomplished in two steps to give 3b. Compound 3b can be converted tocompound 3o according to Scheme 3.

Representative pyridone (ring B=pyridone) containing macrocycles of thisinvention can be prepared as shown in Scheme 17. Compound 17d can beprepared in two steps according to a modified procedure described byResmini (Resmini, M. et al., Tetrahedron Asymmetry, 15:1847 (2004)). Asuitably substituted amino ester 17a can be converted to thecorresponding β-ketophosphonate 17b by treatment with lithiumdimethylmethylphosphonate. Homer-Wadsworth-Emmons reaction of 17b and asuitably substituted aldehyde 17c in the presence of base such aspotassium carbonate in a solvent such as ethanol or tetrahydrofurangives the α,β-unsaturated ketone 17d. Condensation of 17d with1-(ethoxycarbonylmethyl)-pyrdinium chloride or1-(carbamoylmethyl)-pyridinium chloride in the presence of ammoniumacetate in a solvent such as ethanol or glacial acetic acid generatesthe pyridone 17e. The nitro group can be reduced to the aniline 17f withzinc and ammonium chloride in methanol. Alternatively, alkylation of thecesium salt of the pyridone 17e with methyl iodide, followed byreduction of the nitro as described above, can yield the N-Me pyridonederivative 17g. Compounds of the formula 17f and 17g can be converted tocompounds 17h-k, according to Scheme 7, or to compounds 17l-m, accordingto Scheme 14.

Representative pyrimidine (ring B=pyrimidine) containing macrocycles ofthis invention can be prepared as shown in Scheme 18. Condensation ofthe β-ketoester 18b, prepared according to a modified procedure ofMaibaum (J. Org. Chem., 53:869 (1988)), with a suitably substitutedamidine under basic conditions, such as formamidine and sodium methoxidein methanol, yields the pyrimidone 18c. The pyrimidone can be convertedto the chloro pyrimidine 18d in two steps with phosphorus oxychlorideand then reprotection of the amine with Boc-anhydride. Alternatively,the pyrimidone can be converted directly to the corresponding triflate18e with sodium hydride and N-phenyltrifluoromethanesulfonimide.Suzuki-Miyaura coupling between 18d or 18e and an appropriatelysubstituted aryl or heteroaryl boronic acid or ester 7d in the presenceof a base such as potassium phosphate in a solvent mixture, suchdimethylsulfoxide and water, or dimethylformamide, using a precatalystsuch as Pd(dppf)Cl₂.CH₂Cl₂ complex provides 18f. Compounds of theformula 18f can be converted to compounds 18g-h, according to Scheme 7,or to compounds 18i, according to Scheme 14.

Representative pyridazinone (ring B=pyridazinone) containing macrocyclesof this invention can be prepared as shown in Scheme 19. Condensation ofthe potassium salt of 17b with a suitably substituted α-ketoester 19a,which is either commercially available or prepared using a modifiedprocedure described by Domagala (Tetrahedron Lett., 21:4997-5000), in asolvent such as tetrahydrofuran generates the α,β-unsaturated ketonederivative which can then be condensed with a suitably substitutedhydrazine derivative to give pyridazinone 19b. The nitro group can bereduced to the aniline 19c with zinc and ammonium chloride in methanol.Compounds of the formula 19c can be converted to compounds 19d accordingto Scheme 14.

It should be recognized that additional deprotection steps and furtherfunctional group manipulations of compounds obtained via Schemes I-19using methods known in the art will then provide additional compounds ofthis invention.

Purification of intermediates and final products was carried out viaeither normal or reverse phase chromatography. Normal phasechromatography was carried out using prepacked SiO₂ cartridges elutingwith either gradients of hexanes and ethyl acetate or dichloromethaneand methanol unless otherwise indicated. Reverse phase preparative HPLCwas carried out using C18 columns eluting with gradients of Solvent A(90% water, 10% methanol, 0.1% TFA) and Solvent B (10% water, 90%methanol, 0.1% TFA, UV 220 nm) or with gradients of Solvent A (90%water, 10% acetonitrile, 0.1% TFA) and Solvent B (10% water, 90%acetonitrile, 0.1% TFA, UV 220 nm) or with gradients of Solvent A (98%water, 2% acetonitrile, 0.05% TFA) and Solvent B (98% acetonitrile, 2%water, 0.05% TFA, UV 254 nm).

Unless otherwise stated, analysis of final products was carried out byreverse phase analytical HPLC using the Waters SunFire column (3.5 μmC18, 3.0×150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent Bfor 12 min and then 100% Solvent B for 3 min was used. Solvent A is (95%water, 5% acetonitrile, 0.05% TFA) and Solvent B is (5% water, 95%acetonitrile, 0.05% TFA, UV 254 nm). Method B: Agilent ZORBAX® (3.5 μmC18, 4.6×75 mm) eluted at 2.5 mL/min with an 8 min gradient from 100% Ato 100% B (A: 10% methanol, 89.9% water, 0.1% H₃PO₄; B: 10% water, 89.9%methanol, 0.1% H₃PO₄, UV 220 nm). Method C: Waters SunFire column (3.5μm C18, 4.6×150 mm) eluted at 1 mL/min with a gradient from 10-100%Solvent B for 10 min and then 100% Solvent B for 5 min. (A: 0.01 MNH₄HCO₃ in water:methanol 95:5. B: 0.01 M NH₄HCO₃ in water:methanol5:95. UV 254 nm). Method D: Waters SunFire column (3.5 μm C18, 3.0×150mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B for 10 min andthen 100% Solvent B for 5 min was used. Solvent A is (95% water, 5%acetonitrile, 0.05% TFA) and Solvent B is (5% water, 95% acetonitrile,0.05% TFA, UV 254 nm).

IV. Biology

While blood coagulation is essential to the regulation of an organism'shemostasis, it is also involved in many pathological conditions. Inthrombosis, a blood clot, or thrombus, may form and obstruct circulationlocally, causing ischemia and organ damage. Alternatively, in a processknown as embolism, the clot may dislodge and subsequently become trappedin a distal vessel, where it again causes ischemia and organ damage.Diseases arising from pathological thrombus formation are collectivelyreferred to as thromboembolic disorders and include acute coronarysyndrome, unstable angina, myocardial infarction, thrombosis in thecavity of the heart, ischemic stroke, deep vein thrombosis, peripheralocclusive arterial disease, transient ischemic attack, and pulmonaryembolism. In addition, thrombosis occurs on artificial surfaces incontact with blood, including catheters, stents, artificial heartvalves, and hemodialysis membranes.

Some conditions contribute to the risk of developing thrombosis. Forexample, alterations of the vessel wall, changes in the flow of blood,and alterations in the composition of the vascular compartment. Theserisk factors are collectively known as Virchow's triad. (Hemostasis andThrombosis, Basic Principles and Clinical Practice, 5th Edition, p. 853,Colman, R. W. et al., eds., Lippincott Williams & Wilkins (2006))Antithrombotic agents are frequently given to patients at risk ofdeveloping thromboembolic disease because of the presence of one or morepredisposing risk factors from Virchow's triad to prevent formation ofan occlusive thrombus (primary prevention). For example, in anorthopedic surgery setting (e.g., hip and knee replacement), anantithrombotic agent is frequently administered prior to a surgicalprocedure. The antithrombotic agent counterbalances the prothromboticstimulus exerted by vascular flow alterations (stasis), potentialsurgical vessel wall injury, as well as changes in the composition ofthe blood due to the acute phase response related to surgery. Anotherexample of the use of an antithrombotic agent for primary prevention isdosing with aspirin, a platelet activation inhibitor, in patients atrisk for developing thrombotic cardiovascular disease. Well recognizedrisk factors in this setting include age, male gender, hypertension,diabetes mellitus, lipid alterations, and obesity.

Antithrombotic agents are also indicated for secondary prevention,following an initial thrombotic episode. For example, patients withmutations in Factor V (also known as Factor V Leiden) and additionalrisk factors (e.g., pregnancy), are dosed with anticoagulants to preventthe reoccurrence of venous thrombosis. Another example entails secondaryprevention of cardiovascular events in patients with a history of acutemyocardial infarction or acute coronary syndrome. In a clinical setting,a combination of aspirin and clopidogrel (or other thienopyridines) maybe used to prevent a second thrombotic event.

Antithrombotic agents are also given to treat the disease state (i.e.,by arresting its development) after it has already started. For example,patients presenting with deep vein thrombosis are treated withanticoagulants (i.e., heparin, warfarin, or LMWH) to prevent furthergrowth of the venous occlusion. Over time, these agents also cause aregression of the disease state because the balance betweenprothrombotic factors and anticoagulant/profibrinolytic pathways ischanged in favor of the latter. Examples on the arterial vascular bedinclude the treatment of patients with acute myocardial infarction oracute coronary syndrome with aspirin and clopidogrel to prevent furthergrowth of vascular occlusions and eventually leading to a regression ofthrombotic occlusions.

Thus, antithrombotic agents are used widely for primary and secondaryprevention (i.e., prophylaxis or risk reduction) of thromboembolicdisorders, as well as treatment of an already existing thromboticprocess. Drugs that inhibit blood coagulation, or anticoagulants, are“pivotal agents for prevention and treatment of thromboembolicdisorders” (Hirsh, J. et al., Blood, 105:453-463 (2005)).

An alternative way of initiation of coagulation is operative when bloodis exposed to artificial surfaces (e.g., during hemodialysis, “on-pump”cardiovascular surgery, vessel grafts, bacterial sepsis), on cellsurfaces, cellular receptors, cell debris, DNA, RNA, and extracellularmatrices. This process is also termed contact activation. Surfaceabsorption of Factor XII leads to a conformational change in the FactorXII molecule, thereby facilitating activation to proteolytic activeFactor XII molecules (Factor XIIa and Factor XIIf). Factor XIIa (orXIIf) has a number of target proteins, including plasma prekallikreinand Factor XI. Active plasma kallikrein further activates Factor XII,leading to an amplification of contact activation. Alternatively, theserine protease prolylcarboxylpeptidase can activate plasma kallikreincomplexed with high molecular weight kininogen in a multiprotein complexformed on the surface of cells and matrices (Shariat-Madar et al.,Blood, 108:192-199 (2006)). Contact activation is a surface mediatedprocess responsible in part for the regulation of thrombosis andinflammation, and is mediated, at least in part, by fibrinolytic-,complement-, kininogen/kinin-, and other humoral and cellular pathways(for review, Coleman, R., “Contact Activation Pathway”, Hemostasis andThrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001); Schmaier,A. H., “Contact Activation”, Thrombosis and Hemorrhage, pp. 105-128(1998)). The biological relevance of the contact activation system forthromboembolic diseases is supported by the phenotype of Factor XIIdeficient mice. More specifically, Factor XII deficient mice wereprotected from thrombotic vascular occlusion in several thrombosismodels as well as stroke models and the phenotype of the XII deficientmice was identical to XI deficient mice (Renne et al., J. Exp. Med.,202:271-281 (2005); Kleinschmitz et al., J. Exp. Med., 203:513-518(2006)). The fact that Factor XI is down-stream from Factor XIIa,combined with the identical phenotype of the XII and XI deficient micesuggest that the contact activation system could play a major role inFactor XI activation in vivo.

Factor XI is a zymogen of a trypsin-like serine protease and is presentin plasma at a relatively low concentration. Proteolytic activation atan internal R369-I370 bond yields a heavy chain (369 amino acids) and alight chain (238 amino acids). The latter contains a typicaltrypsin-like catalytic triad (H413, D464, and S557). Activation ofFactor XI by thrombin is believed to occur on negatively chargedsurfaces, most likely on the surface of activated platelets. Plateletscontain high affinity (0.8 nM) specific sites (130-500/platelet) foractivated Factor XI. After activation, Factor XIa remains surface boundand recognizes Factor IX as its normal macromolecular substrate.(Galiani, D., Trends Cardiovasc. Med., 10:198-204 (2000))

In addition to the feedback activation mechanisms described above,thrombin activates thrombin activated fibrinolysis inhibitor (TAFI), aplasma carboxypeptidase that cleaves C-terminal lysine and arginineresidues on fibrin, reducing the ability of fibrin to enhancetissue-type plasminogen activator (tPA) dependent plasminogenactivation. In the presence of antibodies to FXIa, clot lysis can occurmore rapidly independent of plasma TAFI concentration. (Bouma, B. N. etal., Thromb. Res., 101:329-354 (2001).) Thus, inhibitors of Factor XIaare expected to be anticoagulant and profibrinolytic.

Further evidence for the anti-thromboembolic effects of targeting FactorXI is derived from mice deficient in Factor XI. It has been demonstratedthat complete fXI deficiency protected mice from ferric chloride(FeCl₃)-induced carotid artery thrombosis (Rosen et al., Thromb.Haemost., 87:774-777 (2002); Wang et al., J. Thromb. Haemost., 3:695-702(2005)). Also, Factor XI deficiency rescues the perinatal lethalphenotype of complete protein C deficiency (Chan et al., Amer. J.Pathology, 158:469-479 (2001)). Furthermore, baboon cross-reactive,function blocking antibodies to human Factor XI protect against baboonarterial —venous shunt thrombosis (Gruber et al., Blood, 102:953-955(2003)). Evidence for an antithrombotic effect of small moleculeinhibitors of Factor XIa is also disclosed in published U.S. PatentApplication No. 2004/0180855A1. Taken together, these studies suggestthat targeting Factor XI will reduce the propensity for thrombotic andthromboembolic diseases.

Genetic evidence indicates that Factor XI is not required for normalhomeostasis, implying a superior safety profile of the Factor XImechanism compared to competing antithrombotic mechanisms. In contrastto hemophilia A (Factor VIII deficiency) or hemophilia B (Factor IXdeficiency), mutations of the Factor XI gene causing Factor XIdeficiency (hemophilia C) result in only a mild to moderate bleedingdiathesis characterized primarily by postoperative or posttraumatic, butrarely spontaneous hemorrhage. Postoperative bleeding occurs mostly intissue with high concentrations of endogenous fibrinolytic activity(e.g., oral cavity, and urogenital system). The majority of the casesare fortuitously identified by preoperative prolongation of aPTT(intrinsic system) without any prior bleeding history.

The increased safety of inhibition of XIa as an anticoagulation therapyis further supported by the fact that Factor XI knock-out mice, whichhave no detectable Factor XI protein, undergo normal development, andhave a normal life span. No evidence for spontaneous bleeding has beennoted. The aPTT (intrinsic system) is prolonged in a gene dose-dependentfashion. Interestingly, even after severe stimulation of the coagulationsystem (tail transection), the bleeding time is not significantlyprolonged compared to wild-type and heterozygous litter mates. (Gailani,D., Frontiers in Bioscience, 6:201-207 (2001); Gailani, D. et al., BloodCoagulation and Fibrinolysis, 8:134-144 (1997).) Taken together, theseobservations suggest that high levels of inhibition of Factor XIa shouldbe well tolerated. This is in contrast to gene targeting experimentswith other coagulation factors, excluding Factor XII.

In vivo activation of Factor XI can be determined by complex formationwith either Cl inhibitor or alpha 1 antitrypsin. In a study of 50patients with acute myocardial infarction (AMI), approximately 25% ofthe patients had values above the upper normal range of the complexELISA. This study can be viewed as evidence that at least in asubpopulation of patients with AMI, Factor XI activation contributes tothrombin formation (Minnema, M. C. et al., Arterioscler. Thromb. Vasc.Biol., 20:2489-2493 (2000)). A second study establishes a positivecorrelation between the extent of coronary arteriosclerosis and FactorXIa in complex with alpha 1 antitrypsin (Murakami, T. et al.,Arterioscler. Thromb. Vasc. Biol., 15:1107-1113 (1995)). In anotherstudy, Factor XI levels above the 90th percentile in patients wereassociated with a 2.2-fold increased risk for venous thrombosis(Meijers, J. C. M. et al., N. Engl. J. Med., 342:696-701 (2000)).

Plasma kallikrein is a zymogen of a trypsin-like serine protease and ispresent in plasma at 35 to 50 μg/mL. The gene structure is similar tothat of Factor XI. Overall, the amino acid sequence of plasma kallikreinhas 58% homology to Factor XI. Proteolytic activation by Factor XIIa atan internal I 389-R390 bond yields a heavy chain (371 amino acids) and alight chain (248 amino acids). The active site of plasma kallikrein iscontained in the light chain. The light chain of plasma kallikreinreacts with protease inhibitors, including alpha 2 macroglobulin andC1-inhibitor. Interestingly, heparin significantly accelerates theinhibition of plasma kallikrein by antithrombin III in the presence ofhigh molecular weight kininogen (HMWK). In blood, the majority of plasmakallikrein circulates in complex with HMWK. Plasma kallikrein cleavesHMWK to liberate bradykinin. Bradykinin release results in increase ofvascular permeability and vasodilation (for review, Coleman, R.,“Contact Activation Pathway”, Hemostasis and Thrombosis, pp. 103-122,Lippincott Williams & Wilkins (2001); Schmaier A. H., “ContactActivation”, Thrombosis and Hemorrhage, pp. 105-128 (1998)).

Also, it is preferred to find new compounds with improved activity in invitro clotting assays, compared with known serine protease inhibitors,such as the activated partial thromboplastin time (aPTT) or prothrombintime (PT) assay. (for a description of the aPTT and PT assays see,Goodnight, S. H. et al., “Screening Tests of Hemostasis”, Disorders ofThrombosis and Hemostasis: A Clinical Guide, 2nd Edition, pp. 41-51,McGraw-Hill, New York (2001)).

It is also desirable and preferable to find compounds with advantageousand improved characteristics compared with known serine proteaseinhibitors, in one or more of the following categories that are given asexamples, and are not intended to be limiting: (a) pharmacokineticproperties, including oral bioavailability, half life, and clearance;(b) pharmaceutical properties; (c) dosage requirements; (d) factors thatdecrease blood concentration peak-to-trough characteristics; (e) factorsthat increase the concentration of active drug at the receptor; (f)factors that decrease the liability for clinical drug-drug interactions;(g) factors that decrease the potential for adverse side-effects,including selectivity versus other biological targets; and (h) factorsthat improve manufacturing costs or feasibility.

Pre-clinical studies demonstrated significant antithrombotic effects ofsmall molecule Factor XIa inhibitors in rabbit and rat model of arterialthrombosis, at doses that preserved hemostasis. (Wong P. C. et al.,American Heart Association Scientific Sessions, Abstract No. 6118, Nov.12-15, 2006; Schumacher, W. et al., J. Thromb. Haemost., 3(Suppl.1):P1228 (2005); Schumacher, W. A. et al., Eur. J. Pharmacol., 167-174(2007)). Furthermore, it was observed that in vitro prolongation of theaPTT by specific XIa inhibitors is a good predictor of efficacy in ourthrombosis models. Thus, the in vitro aPTT test can be used as asurrogate for efficacy in vivo.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” cover the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit Factor XIa and/or plasma kallikreinand/or to prevent or treat the disorders listed herein. When applied toa combination, the term refers to combined amounts of the activeingredients that result in the preventive or therapeutic effect, whetheradministered in combination, serially, or simultaneously.

The term “thrombosis”, as used herein, refers to formation or presenceof a thrombus (pl. thrombi); clotting within a blood vessel that maycause ischemia or infarction of tissues supplied by the vessel. The term“embolism”, as used herein, refers to sudden blocking of an artery by aclot or foreign material that has been brought to its site of lodgmentby the blood current. The term “thromboembolism”, as used herein, refersto obstruction of a blood vessel with thrombotic material carried by theblood stream from the site of origin to plug another vessel. The term“thromboembolic disorders” entails both “thrombotic” and “embolic”disorders (defined above).

The term “thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascular orcerebrovascular thromboembolic disorders, and thromboembolic disordersin the chambers of the heart or in the peripheral circulation. The term“thromboembolic disorders” as used herein also includes specificdisorders selected from, but not limited to, unstable angina or otheracute coronary syndromes, atrial fibrillation, first or recurrentmyocardial infarction, ischemic sudden death, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. The medical implantsor devices include, but are not limited to: prosthetic valves,artificial valves, indwelling catheters, stents, blood oxygenators,shunts, vascular access ports, ventricular assist devices and artificialhearts or heart chambers, and vessel grafts. The procedures include, butare not limited to:

cardiopulmonary bypass, percutaneous coronary intervention, andhemodialysis. In another embodiment, the term “thromboembolic disorders”includes acute coronary syndrome, stroke, deep vein thrombosis, andpulmonary embolism.

In another embodiment, the present invention provides a method for thetreatment of a thromboembolic disorder, wherein the thromboembolicdisorder is selected from unstable angina, an acute coronary syndrome,atrial fibrillation, myocardial infarction, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. In anotherembodiment, the present invention provides a method for the treatment ofa thromboembolic disorder, wherein the thromboembolic disorder isselected from acute coronary syndrome, stroke, venous thrombosis, atrialfibrillation, and thrombosis resulting from medical implants anddevices.

In another embodiment, the present invention provides a method for theprimary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, myocardial infarction, ischemicsudden death, transient ischemic attack, stroke, atherosclerosis,peripheral occlusive arterial disease, venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary arterialthrombosis, cerebral arterial thrombosis, cerebral embolism, kidneyembolism, pulmonary embolism, and thrombosis resulting from medicalimplants, devices, or procedures in which blood is exposed to anartificial surface that promotes thrombosis. In another embodiment, thepresent invention provides a method for the primary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, venous thrombosis, and thrombosisresulting from medical implants and devices.

In another embodiment, the present invention provides a method for thesecondary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, recurrent myocardial infarction,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis. In another embodiment, the presentinvention provides a method for the secondary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, atrial fibrillation and venousthrombosis.

The term “stroke”, as used herein, refers to embolic stroke oratherothrombotic stroke arising from occlusive thrombosis in the carotidcommunis, carotid intema, or intracerebral arteries.

It is noted that thrombosis includes vessel occlusion (e.g., after abypass) and reocclusion (e.g., during or after percutaneous transluminalcoronary angioplasty). The thromboembolic disorders may result fromconditions including but not limited to atherosclerosis, surgery orsurgical complications, prolonged immobilization, arterial fibrillation,congenital thrombophilia, cancer, diabetes, effects of medications orhormones, and complications of pregnancy.

Thromboembolic disorders are frequently associated with patients withatherosclerosis. Risk factors for atherosclerosis include but are notlimited to male gender, age, hypertension, lipid disorders, and diabetesmellitus. Risk factors for atherosclerosis are at the same time riskfactors for complications of atherosclerosis, i.e., thromboembolicdisorders.

Similarly, arterial fibrillation is frequently associated withthromboembolic disorders. Risk factors for arterial fibrillation andsubsequent thromboembolic disorders include cardiovascular disease,rheumatic heart disease, nonrheumatic mitral valve disease, hypertensivecardiovascular disease, chronic lung disease, and a variety ofmiscellaneous cardiac abnormalities as well as thyrotoxicosis.

Diabetes mellitus is frequently associated with atherosclerosis andthromboembolic disorders. Risk factors for the more common type 2include but are not limited to are family history, obesity, physicalinactivity, race/ethnicity, previously impaired fasting glucose orglucose tolerance test, history of gestational diabetes mellitus ordelivery of a “big baby”, hypertension, low HDL cholesterol, andpolycystic ovary syndrome.

Risk factors for congenital thrombophilia include gain of functionmutations in coagulation factors or loss of function mutations in theanticoagulant- or fibrinolytic pathways.

Thrombosis has been associated with a variety of tumor types, e.g.,pancreatic cancer, breast cancer, brain tumors, lung cancer, ovariancancer, prostate cancer, gastrointestinal malignancies, and Hodgkins ornon-Hodgkins lymphoma. Recent studies suggest that the frequency ofcancer in patients with thrombosis reflects the frequency of aparticular cancer type in the general population (Levitan, N. et al.,Medicine (Baltimore), 78(5):285-291 (1999); Levine M. et al., N. Engl.J. Med., 334(11):677-681 (1996); Blom, J. W. et al., JAMA,293(6):715-722 (2005)). Hence, the most common cancers associated withthrombosis in men are prostate, colorectal, brain, and lung cancer, andin women are breast, ovary, and lung cancer. The observed rate of venousthromboembolism (VTE) in cancer patients is significant. The varyingrates of VTE between different tumor types are most likely related tothe selection of the patient population. Cancer patients at risk forthrombosis may possess any or all of the following risk factors: (i) thestage of the cancer (i.e., presence of metastases), (ii) the presence ofcentral vein catheters, (iii) surgery and anticancer therapies includingchemotherapy, and (iv) hormones and antiangiogenic drugs. Thus, it iscommon clinical practice to dose patients having advanced tumors withheparin or low molecular heparin to prevent thromboembolic disorders. Anumber of low molecular heparin preparations have been approved by theFDA for these indications.

There are three main clinical situations when considering the preventionof VTE in a medical cancer patient: (i) the patient is bedridden forprolonged periods of time; (ii) the ambulatory patient is receivingchemotherapy or radiation; and (iii) the patient is with indwellingcentral vein catheters. Unfractionated heparin (UFH) and low molecularweight heparin (LMWH) are effective antithrombotic agents in cancerpatients undergoing surgery. (Mismetti, P. et al., Brit. J. Surg.,88:913-930 (2001).)

A. In Vitro Assays

The effectiveness of compounds of the present invention as inhibitors ofthe coagulation Factors XIa, VIIa, IXa, Xa, XIIa, plasma kallikrein orthrombin, can be determined using a relevant purified serine protease,respectively, and an appropriate synthetic substrate. The rate ofhydrolysis of the chromogenic or fluorogenic substrate by the relevantserine protease was measured both in the absence and presence ofcompounds of the present invention. Hydrolysis of the substrate resultedin the release of pNA (para nitroaniline), which was monitoredspectrophotometrically by measuring the increase in absorbance at 405nm, or the release of AMC (amino methylcoumarin), which was monitoredspectrofluorometrically by measuring the increase in emission at 460 nmwith excitation at 380 nm. A decrease in the rate of absorbance orfluorescence change in the presence of inhibitor is indicative of enzymeinhibition. Such methods are known to one skilled in the art. Theresults of this assay are expressed as the inhibitory constant, K_(i).

Factor XIa determinations were made in 50 mM HEPES buffer at pH 7.4containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethyleneglycol; JT Baker or Fisher Scientific). Determinations were made usingpurified human Factor XIa at a final concentration of 25-200 pM(Haematologic Technologies) and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; CHROMOGENIX® or AnaSpec) at a concentration of0.0002-0.001 M.

Factor VIIa determinations were made in 0.005 M calcium chloride, 0.15 Msodium chloride, 0.05 M HEPES buffer containing 0.1% PEG 8000 at a pH of7.5. Determinations were made using purified human Factor VIIa(Haematologic Technologies) or recombinant human Factor VIIa (NovoNordisk) at a final assay concentration of 0.5-10 nM, recombinantsoluble tissue factor at a concentration of 10-40 nM and the syntheticsubstrate H-D-Ile-Pro-Arg-pNA (S-2288; CHROMOGENIX® or BMPM-2; AnaSpec)at a concentration of 0.001-0.0075 M.

Factor IXa determinations were made in 0.005 M calcium chloride, 0.1 Msodium chloride, 0.0000001 M Refludan (Berlex), 0.05 M TRIS base and0.5% PEG 8000 at a pH of 7.4. Refludan was added to inhibit smallamounts of thrombin in the commercial preparations of human Factor IXa.Determinations were made using purified human Factor IXa (HaematologicTechnologies) at a final assay concentration of 20-100 nM and thesynthetic substrate PCIXA2100-B (CenterChem) or Pefafluor IXa 3688(H-D-Leu-Ph′Gly-Arg-AMC; CenterChem) at a concentration of 0.0004-0.0005M.

Factor Xa determinations were made in 0.1 M sodium phosphate buffer at apH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human Factor Xa (HaematologicTechnologies) at a final assay concentration of 150-1000 pM and thesynthetic substrate S-2222 (Bz-Ile-Glu (gamma-OMe, 50%)-Gly-Arg-pNA;CHROMOGENIX®) at a concentration of 0.0002-0.00035 M.

Factor XIIa determinations were made in 50 mM HEPES buffer at pH 7.4containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000. Determinations weremade using purified human Factor XIIa at a final concentration of 4 nM(American Diagnostica) and the synthetic substrate SPECTROZYME® #312(H-D-CHT-Gly-L-Arg-pNA.2AcOH; American Diagnostica) at a concentrationof 0.00015 M.

Plasma kallikrein determinations were made in 0.1 M sodium phosphatebuffer at a pH of 7.5 containing 0.1-0.2 M sodium chloride and 0.5% PEG8000. Determinations were made using purified human kallikrein (EnzymeResearch Laboratories) at a final assay concentration of 200 pM and thesynthetic substrate S-2302 (H-(D)-Pro-Phe-Arg-pNA; CHROMOGENIX®) at aconcentration of 0.00008-0.0004 M. The K_(m) value used for calculationof K_(i) was 0.00005 to 0.00007 M.

Thrombin determinations were made in 0.1 M sodium phosphate buffer at apH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human alpha thrombin(Haematologic Technologies or Enzyme Research Laboratories) at a finalassay concentration of 200-250 pM and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; CHROMOGENIX® or AnaSpec) at a concentration of0.0002-0.0004 M.

The Michaelis constant, K_(m), for substrate hydrolysis by eachprotease, was determined at 25° C. using the method of Lineweaver andBurk. Values of K_(i) were determined by allowing the protease to reactwith the substrate in the presence of the inhibitor. Reactions wereallowed to go for periods of 20-180 minutes (depending on the protease)and the velocities (rate of absorbance or fluorescence change versustime) were measured. The following relationships were used to calculateK_(i) values:(v _(o) −v _(s))/v _(s) =I/(K _(i)(1+S/K _(m))) for a competitiveinhibitor with one binding site; orv _(s) /v _(o) =A+((B−A)/1+((IC ₅₀/(I)n))); andK _(i) ═IC ₅₀/(1+S/K _(m)) for a competitive inhibitorwhere:

v_(o) is the velocity of the control in the absence of inhibitor;

v_(s) is the velocity in the presence of inhibitor;

I is the concentration of inhibitor;

A is the minimum activity remaining (usually locked at zero);

B is the maximum activity remaining (usually locked at 1.0);

n is the Hill coefficient, a measure of the number and cooperativity ofpotential inhibitor binding sites;

IC₅₀ is the concentration of inhibitor that produces 50% inhibitionunder the assay conditions;

K_(i) is the dissociation constant of the enzyme:inhibitor complex;

S is the concentration of substrate; and

K_(m) is the Michaelis constant for the substrate.

The selectivity of a compound may be evaluated by taking the ratio ofthe K_(i) value for a given protease with the K_(i) value for theprotease of interest (i.e., selectivity for FXIa versus protease P═K_(i)for protease P/K_(i) for FXIa). Compounds with selectivity ratios >20are considered selective. Compounds with selectivity ratios >100 arepreferred, and compounds with selectivity ratios >500 are morepreferred.

The effectiveness of compounds of the present invention as inhibitors ofcoagulation can be determined using a standard or modified clottingassay. An increase in the plasma clotting time in the presence ofinhibitor is indicative of anticoagulation. Relative clotting time isthe clotting time in the presence of an inhibitor divided by theclotting time in the absence of an inhibitor. The results of this assaymay be expressed as IC1.5x or IC2x, the inhibitor concentration requiredto increase the clotting time by 50 or 100 percent, respectively. TheIC1.5x or IC2x is found by linear interpolation from relative clottingtime versus inhibitor concentration plots using inhibitor concentrationthat spans the IC1.5x or IC2x.

Clotting times are determined using citrated normal human plasma as wellas plasma obtained from a number of laboratory animal species (e.g.,rat, or rabbit). A compound is diluted into plasma beginning with a 10mM DMSO stock solution. The final concentration of DMSO is less than 2%.Plasma clotting assays are performed in an automated coagulationanalyzer (Sysmex, Dade-Behring, Illinois). Similarly, clotting times canbe determined from laboratory animal species or humans dosed withcompounds of the invention.

Activated Partial Thromboplastin Time (aPTT) is determined using ALEXIN®(Trinity Biotech, Ireland) or ACTIN® (Dade-Behring, Illinois) followingthe directions in the package insert. Plasma (0.05 mL) is warmed to 37°C. for 1 minute. ALEXIN® or ACTIN® (0.05 mL) is added to the plasma andincubated for an additional 2 to 5 minutes. Calcium chloride (25 mM,0.05 mL) is added to the reaction to initiate coagulation. The clottingtime is the time in seconds from the moment calcium chloride is addeduntil a clot is detected.

Prothrombin Time (PT) is determined using thromboplastin (ThromboplastinC Plus, Dade-Behring, Illinois) following the directions in the packageinsert. Plasma (0.05 mL) is warmed to 37° C. for 1 minute.Thromboplastin (0.1 mL) is added to the plasma to initiate coagulation.The clotting time is the time in seconds from the moment thromboplastinis added until a clot is detected.

The exemplified Examples disclosed below were tested in the Factor XIaassay described above and found having Factor XIa inhibitory activity. Arange of Factor XIa inhibitory activity (K_(i) values) of ≤10 μM (10000nM) was observed. Table 1 below lists Factor XIa K_(i) values measuredfor the following examples.

TABLE 1 Example No. Factor XIa Ki (nM)  1 2983  3 6174  4 636  6 34  9249  10 <5  11 6  19 96  21 4515  61 <5  89 1057  90 <5  93 <5 121 <5122 25 136 962 137 192 138 20 167 157 I-4 <5 I-5 <5 I-9 1872 I-10 217I-13 311 I-14 2920 I-17 351 I-21 <5 I-57 6.6 I-59 <5 I-60 616 I-67 203I-70 270 I-72 289 I-77 <5 I-80 <5 I-84 580 I-94 3851 I-99 1322 I-104 435I-106 24 I-107 29 I-108 3869 I-114 296 I-115 <5 I-121 736 I-124 <5 I-134<5 I-136 183 I-137 2979 I-151 <5 I-152 21 I-153 1652 I-183 4949 I-2112171 I-227 <5 I-242 456 I-251 <5 I-258 947 I-262 675 I-265 133 I-268 9I-270 1745 I-278 <5 I-284 102 I-299 19 I-309 9 I-311 <5 II-3 <5 II-4 111II-10 23 II-13 <5 II-15 4156 II-18 572 II-35 <5 II-43 938 II-58 21 II-62<5B. In Vivo Assays

The effectiveness of compounds of the present invention asantithrombotic agents can be determined using relevant in vivothrombosis models, including In Vivo Electrically-induced Carotid ArteryThrombosis Models and In Vivo Rabbit Arterio-venous Shunt ThrombosisModels.

a. In Vivo Electrically-induced Carotid Artery Thrombosis (ECAT) Model

The rabbit ECAT model, described by Wong et al. (J. Pharmacol. Exp.Ther., 295:212-218 (2000)), can be used in this study. Male New ZealandWhite rabbits are anesthetized with ketamine (50 mg/kg+50 mg/kg/h IM)and xylazine (10 mg/kg+10 mg/kg/h IM). These anesthetics aresupplemented as needed. An electromagnetic flow probe is placed on asegment of an isolated carotid artery to monitor blood flow. Test agentsor vehicle will be given (i.v., i.p., s.c., or orally) prior to or afterthe initiation of thrombosis. Drug treatment prior to initiation ofthrombosis is used to model the ability of test agents to prevent andreduce the risk of thrombus formation, whereas dosing after initiationis used to model the ability to treat existing thrombotic disease.Thrombus formation is induced by electrical stimulation of the carotidartery for 3 min at 4 mA using an external stainless-steel bipolarelectrode. Carotid blood flow is measured continuously over a 90-minperiod to monitor thrombus-induced occlusion. Total carotid blood flowover 90 min is calculated by the trapezoidal rule. Average carotid flowover 90 min is then determined by converting total carotid blood flowover 90 min to percent of total control carotid blood flow, which wouldresult if control blood flow had been maintained continuously for 90min. The ED₅₀ (dose that increased average carotid blood flow over 90min to 50% of the control) of compounds are estimated by a nonlinearleast square regression program using the Hill sigmoid E_(max) equation(DeltaGraph; SPSS Inc., Chicago, Ill.).

b. In Vivo Rabbit Arterio-venous (AV) Shunt Thrombosis Model

The rabbit AV shunt model, described by Wong et al. (Wong, P. C. et al.,J Pharmacol. Exp. Ther., 292:351-357 (2000)), can be used in this study.Male New Zealand White rabbits are anesthetized with ketamine (50mg/kg+50 mg/kg/h IM) and xylazine (10 mg/kg+10 mg/kg/h IM). Theseanesthetics are supplemented as needed. The femoral artery, jugular veinand femoral vein are isolated and catheterized. A saline-filled AV shuntdevice is connected between the femoral arterial and the femoral venouscannulae. The AV shunt device consists of an outer piece of tygon tubing(length=8 cm; internal diameter=7.9 mm) and an inner piece of tubing(length=2.5 cm; internal diameter=4.8 mm). The AV shunt also contains an8-cm-long 2-0 silk thread (Ethicon, Somerville, N.J.). Blood flows fromthe femoral artery via the AV-shunt into the femoral vein. The exposureof flowing blood to a silk thread induces the formation of a significantthrombus. Forty minutes later, the shunt is disconnected and the silkthread covered with thrombus is weighed. Test agents or vehicle will begiven (i.v., i.p., s.c., or orally) prior to the opening of the AVshunt. The percentage inhibition of thrombus formation is determined foreach treatment group. The ID₅₀ values (dose that produces 50% inhibitionof thrombus formation) are estimated by a nonlinear least squareregression program using the Hill sigmoid E_(max) equation (DeltaGraph;SPSS Inc., Chicago, Ill.).

The anti-inflammatory effect of these compounds can be demonstrated inan Evans Blue dye extravasation assay using C1-esterase inhibitordeficient mice. In this model, mice are dosed with a compound of thepresent invention, Evans Blue dye is injected via the tail vein, andextravasation of the blue dye is determined by spectrophotometric meansfrom tissue extracts.

The ability of the compounds of the current invention to reduce orprevent the systemic inflammatory response syndrome, for example, asobserved during on-pump cardiovascular procedures, can be tested in invitro perfusion systems, or by on-pump surgical procedures in largermammals, including dogs and baboons. Read-outs to assess the benefit ofthe compounds of the present invention include for example reducedplatelet loss, reduced platelet/white blood cell complexes, reducedneutrophil elastase levels in plasma, reduced activation of complementfactors, and reduced activation and/or consumption of contact activationproteins (plasma kallikrein, Factor XII, Factor XI, high molecularweight kininogen, C1-esterase inhibitors).

The compounds of the present invention may also be useful as inhibitorsof additional serine proteases, notably human thrombin, human plasmakallikrein and human plasmin. Because of their inhibitory action, thesecompounds are indicated for use in the prevention or treatment ofphysiological reactions, including blood coagulation, fibrinolysis,blood pressure regulation and inflammation, and wound healing catalyzedby the aforesaid class of enzymes. Specifically, the compounds haveutility as drugs for the treatment of diseases arising from elevatedthrombin activity of the aforementioned serine proteases, such asmyocardial infarction, and as reagents used as anticoagulants in theprocessing of blood to plasma for diagnostic and other commercialpurposes.

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Remington's Pharmaceutical Sciences, 18th Edition (1990).

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 1000 mg/kg of body weight, preferably between about0.01 to about 100 mg/kg of body weight per day, and most preferablybetween about 0.1 to about 20 mg/kg/day. Intravenously, the mostpreferred doses will range from about 0.001 to about 10 mg/kg/minuteduring a constant rate infusion. Compounds of this invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three, or four times daily.

Compounds of this invention can also be administered by parenteraladministration (e.g., intra-venous, intra-arterial, intramuscularly, orsubcutaneously. When administered intra-venous or intra-arterial, thedose can be given continuously or intermittent. Furthermore, formulationcan be developed for intramuscularly and subcutaneous delivery thatensure a gradual release of the active pharmaceutical ingredient.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 1000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 toabout 100 milligrams of the compound of the present invention and about0.1 to about 100 milligrams per kilogram of patient body weight. For atablet dosage form, the compounds of this invention generally may bepresent in an amount of about 5 to about 100 milligrams per dosage unit,and the second anti-coagulant in an amount of about 1 to about 50milligrams per dosage unit.

Where the compounds of the present invention are administered incombination with an anti-platelet agent, by way of general guidance,typically a daily dosage may be about 0.01 to about 25 milligrams of thecompound of the present invention and about 50 to about 150 milligramsof the anti-platelet agent, preferably about 0.1 to about 1 milligramsof the compound of the present invention and about 1 to about 3milligrams of antiplatelet agents, per kilogram of patient body weight.

Where the compounds of the present invention are administered incombination with thrombolytic agent, typically a daily dosage may beabout 0.1 to about 1 milligrams of the compound of the presentinvention, per kilogram of patient body weight and, in the case of thethrombolytic agents, the usual dosage of the thrombolyic agent whenadministered alone may be reduced by about 50-80% when administered witha compound of the present invention.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom potassium channel openers, potassium channel blockers, calciumchannel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmicagents, antiatherosclerotic agents, anticoagulants, antithromboticagents, prothrombolytic agents, fibrinogen antagonists, diuretics,antihypertensive agents, ATPase inhibitors, mineralocorticoid receptorantagonists, phospodiesterase inhibitors, antidiabetic agents,anti-inflammatory agents, antioxidants, angiogenesis modulators,antiosteoporosis agents, hormone replacement therapies, hormone receptormodulators, oral contraceptives, antiobesity agents, antidepressants,antianxiety agents, antipsychotic agents, antiproliferative agents,antitumor agents, antiulcer and gastroesophageal reflux disease agents,growth hormone agents and/or growth hormone secretagogues, thyroidmimetics, anti-infective agents, antiviral agents, antibacterial agents,antifungal agents, cholesterol/lipid lowering agents and lipid profiletherapies, and agents that mimic ischemic preconditioning and/ormyocardial stunning, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom an antiarrhythmic agent, an anti-hypertensive agent, ananti-coagulant agent, an anti-platelet agent, a thrombin inhibitingagent, a thrombolytic agent, a fibrinolytic agent, a calcium channelblocker, a potassium channel blocker, a cholesterol/lipid loweringagent, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom warfarin, unfractionated heparin, low molecular weight heparin,synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen,naproxen, sulindac, indomethacin, mefenamate, dipyridamol, droxicam,diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel,tirofiban, eptifibatide, abciximab, melagatran, ximelagatran,disulfatohirudin, tissue plasminogen activator, modified tissueplasminogen activator, anistreplase, urokinase, and streptokinase, or acombination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition wherein the additional therapeutic agent is anantihypertensive agent selected from ACE inhibitors, AT-1 receptorantagonists, beta-adrenergic receptor antagonists, ETA receptorantagonists, dual ETA/AT-1 receptor antagonists, renin inhibitors(alliskerin) and vasopepsidase inhibitors, an antiarrythmic agentselected from IKur inhibitors, an anticoagulant selected from thrombininhibitors, antithrombin-III activators, heparin co-Factor IIactivators, other Factor XIa inhibitors, other kallikrein inhibitors,plasminogen activator inhibitor (PAI-1) antagonists, thrombinactivatable fibrinolysis inhibitor (TAFI) inhibitors, Factor VIIainhibitors, Factor IXa inhibitors, and Factor Xa inhibitors, or anantiplatelet agent selected from GPIIb/IIIa blockers, GP Ib/IX blockers,protease activated receptor 1 (PAR-1) antagonists, protease activatedreceptor4 (PAR-4) antagonists, prostaglandin E2 receptor EP3antagonists, collagen receptor antagonists, phosphodiesterase-IIIinhibitors, P2Y₁ receptor antagonists, P2Y₁₂ antagonists, thromboxanereceptor antagonists, cyclooxygense-1 inhibitors, and aspirin, or acombination thereof.

In another embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, wherein the additional therapeutic agent is theanti-platelet agent clopidogrel.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

Compounds that can be administered in combination with the compounds ofthe present invention include, but are not limited to, anticoagulants,anti-thrombin agents, anti-platelet agents, fibrinolytics, hypolipidemicagents, antihypertensive agents, and anti-ischemic agents.

Other anticoagulant agents (or coagulation inhibitory agents) that maybe used in combination with the compounds of this invention includewarfarin, heparin (either unfractionated heparin or any commerciallyavailable low molecular weight heparin, for example LOVENOX®), syntheticpentasaccharide, direct acting thrombin inhibitors including hirudin andargatroban, as well as other Factor VIIa inhibitors, Factor IXainhibitors, Factor Xa inhibitors (e.g., ARIXTRA®, apixaban, rivaroxaban,LY-517717, DU-176b, DX-9065a, and those disclosed in WO 98/57951, WO03/026652, WO 01/047919, and WO 00/076970), Factor XIa inhibitors, andinhibitors of activated TAFI and PAI-1 known in the art.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function, for example, byinhibiting the aggregation, adhesion or granule-content secretion ofplatelets. Such agents include, but are not limited to, the variousknown non-steroidal anti-inflammatory drugs (NSAIDs) such asacetaminophen, aspirin, codeine, diclofenac, droxicam, fentaynl,ibuprofen, indomethacin, ketorolac, mefenamate, morphine, naproxen,phenacetin, piroxicam, sufentanyl, sulfinpyrazone, sulindac, andpharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDs,aspirin (acetylsalicylic acid or ASA) and piroxicam are preferred. Othersuitable platelet inhibitory agents include glycoprotein IIb/IIIaantagonists (e.g., tirofiban, eptifibatide, abciximab, and integrelin),thromboxane-A2-receptor antagonists (e.g., ifetroban),thromboxane-A-synthetase inhibitors, phosphodiesterase-III (PDE-III)inhibitors (e.g., dipyridamole, cilostazol), and PDE-V inhibitors (suchas sildenafil), protease-activated receptor 1 (PAR-1) antagonists (e.g.,E-5555, SCH-530348, SCH-203099, SCH-529153 and SCH-205831), andpharmaceutically acceptable salts or prodrugs thereof.

Other examples of suitable anti-platelet agents for use in combinationwith the compounds of the present invention, with or without aspirin,are ADP (adenosine diphosphate) receptor antagonists, preferablyantagonists of the purinergic receptors P2Y₁ and P2Y₁₂, with P2Y₁₂ beingeven more preferred. Preferred P2Y₁₂ receptor antagonists includeclopidogrel, ticlopidine, prasugrel, ticagrelor, and cangrelor, andpharmaceutically acceptable salts or prodrugs thereof. Ticlopidine andclopidogrel are also preferred compounds since they are known to be moregentle than aspirin on the gastro-intestinal tract in use. Clopidogrelis an even more preferred agent.

A preferred example is a triple combination of a compound of the presentinvention, aspirin, and another anti-platelet agent. Preferably, theanti-platelet agent is clopidogrel or prasugrel, more preferablyclopidogrel.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the secretion of platelet granule contents including serotonin)and/or fibrin formation are disrupted. A number of thrombin inhibitorsare known to one of skill in the art and these inhibitors arecontemplated to be used in combination with the present compounds. Suchinhibitors include, but are not limited to, boroarginine derivatives,boropeptides, heparins, hirudin, argatroban, dabigatran, AZD-0837, andthose disclosed in WO 98/37075 and WO 02/044145, and pharmaceuticallyacceptable salts and prodrugs thereof. Boroarginine derivatives andboropeptides include N-acetyl and peptide derivatives of boronic acid,such as C-terminal a-aminoboronic acid derivatives of lysine, omithine,arginine, homoarginine and corresponding isothiouronium analogs thereof.The term hirudin, as used herein, includes suitable derivatives oranalogs of hirudin, referred to herein as hirulogs, such asdisulfatohirudin.

The term thrombolytic (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator (TPA,natural or recombinant) and modified forms thereof, anistreplase,urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), FactorVIIa inhibitors, thrombin inhibitors, inhibitors of Factors IXa, Xa, andXIa, PAI-I inhibitors (i.e., inactivators of tissue plasminogenactivator inhibitors), inhibitors of activated TAFI, alpha-2-antiplasmininhibitors, and anisoylated plasminogen streptokinase activator complex,including pharmaceutically acceptable salts or prodrugs thereof. Theterm anistreplase, as used herein, refers to anisoylated plasminogenstreptokinase activator complex, as described, for example, in EuropeanPatent Application No. 028489, the disclosure of which is herebyincorporated herein by reference herein. The term urokinase, as usedherein, is intended to denote both dual and single chain urokinase, thelatter also being referred to herein as prourokinase.

Examples of suitable cholesterol/lipid lowering agents and lipid profiletherapies for use in combination with the compounds of the presentinvention include HMG-CoA reductase inhibitors (e.g., pravastatin,lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, andother statins), low-density lipoprotein (LDL) receptor activitymodulators (e.g., HOE-402, PCSK9 inhibitors), bile acid sequestrants(e.g., cholestyramine and colestipol), nicotinic acid or derivativesthereof (e.g., NIASPAN®), GPR109B (nicotinic acid receptor) modulators,fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrateand benzafibrate) and other peroxisome proliferator-activated receptors(PPAR) alpha modulators, PPARdelta modulators (e.g., GW-501516),PPARgamma modulators (e.g., rosiglitazone), compounds that have multiplefunctionality for modulating the activities of various combinations ofPPARalpha, PPARgamma and PPARdelta, probucol or derivatives thereof(e.g., AGI-1067), cholesterol absorption inhibitors and/or Niemann-PickC1-like transporter inhibitors (e.g., ezetimibe), cholesterol estertransfer protein inhibitors (e.g., CP-529414), squalene synthaseinhibitors and/or squalene epoxidase inhibitors or mixtures thereof,acyl coenzyme A: cholesteryl acyltransferase (ACAT) 1 inhibitors, ACAT2inhibitors, dual ACAT1/2 inhibitors, ileal bile acid transportinhibitors (or apical sodium co-dependent bile acid transportinhibitors), microsomal triglyceride transfer protein inhibitors,liver-X-receptor (LXR) alpha modulators, LXRbeta modulators, LXR dualalpha/beta modulators, FXR modulators, omega 3 fatty acids (e.g.,3-PUFA), plant stanols and/or fatty acid esters of plant stanols (e.g.,sitostanol ester used in BENECOL® margarine), endothelial lipaseinhibitors, and HDL functional mimetics which activate reversecholesterol transport (e.g., apoAI derivatives or apoAI peptidemimetics).

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of thrombin, Factor VIIa, IXa,Xa, XIa, and/or plasma kallikrein. Such compounds may be provided in acommercial kit, for example, for use in pharmaceutical researchinvolving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasma kallikrein.XIa. For example, a compound of the present invention could be used as areference in an assay to compare its known activity to a compound withan unknown activity. This would ensure the experimentor that the assaywas being performed properly and provide a basis for comparison,especially if the test compound was a derivative of the referencecompound. When developing new assays or protocols, compounds accordingto the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein. For example, the presence of thrombin, Factor VIIa, IXa, XaXIa, and/or plasma kallikrein in an unknown sample could be determinedby addition of the relevant chromogenic substrate, for example S2366 forFactor XIa, to a series of solutions containing test sample andoptionally one of the compounds of the present invention. If productionof pNA is observed in the solutions containing test sample, but not inthe presence of a compound of the present invention, then one wouldconclude Factor XIa was present.

Extremely potent and selective compounds of the present invention, thosehaving K_(i) values less than or equal to 0.001 μM against the targetprotease and greater than or equal to 0.1 μM against the otherproteases, may also be used in diagnostic assays involving thequantitation of thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein in serum samples. For example, the amount of Factor XIa inserum samples could be determined by careful titration of proteaseactivity in the presence of the relevant chromogenic substrate, S2366,with a potent and selective Factor XIa inhibitor of the presentinvention.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a thromboembolic and/or inflammatorydisorder (as defined previously). In another embodiment, the packageinsert states that the pharmaceutical composition can be used incombination (as defined previously) with a second therapeutic agent totreat a thromboembolic and/or inflammatory disorder. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof. The following Examples have been prepared, isolated andcharacterized using the methods disclosed herein.

INTERMEDIATE 1 (E)-2,5-Dioxopyrrolidin-1-yl3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylate

The synthesis was described as Intermediate 1 in PCT InternationalApplication No. WO 2009/114677 published Sep. 17, 2009.

INTERMEDIATE 2 (E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acrylic acid

The synthesis was described as Intermediate 1B in PCT InternationalApplication No. WO 2009/114677 published Sep. 17, 2009.

INTERMEDIATE 3 (E)-3-(3-Chloro-2-fluoro-6-tetrazol-1-yl-phenyl)-acrylicacid 2,5-dioxo-pyrrolidin-1-yl ester

Intermediate 3A.(E)-3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylic acid: Thesynthesis of Intermediate 3A was described as Intermediate 7 in PCTInternational Application No. WO 2009/114677 published Sep. 17, 2009.

Intermediate 3. To a slightly turbid mixture of Intermediate 3A (1.0 g,3.72 mmol) in THF (18.70 mL) and DMF (1.870 mL) was added1-hydroxypyrrolidine-2,5-dione (0.471 g, 4.09 mmol) and DIC (0.638 mL,4.09 mmol). The reaction was stirred at rt and a white precipitateformed overtime. The solid was collected by suction filtration andwashed with MeOH, water, MeOH, air-dried, and dried under vacuum to giveIntermediate 3 (0.98 g, 72.0% yield), as a white solid. MS (ESI) m/z:366.2 (M+H)⁺.

INTERMEDIATE 4 (E)-3-(2-Acetyl-5-chlorophenyl)acrylic acid

Intermediate 4A. (E)-tert-Butyl 3-(2-acetyl-5-chlorophenyl)acrylate: Toa degassed solution of 1-(2-bromo-4-chlorophenyl)ethanone (1.0 g, 4.28mmol), tributylamine (2.041 mL, 8.57 mmol), and tert-butyl acrylate(1.255 mL, 8.57 mmol) in DMF (10 mL) was added palladium on carbon(0.456 g, 0.428 mmol) and palladium(II) acetate (0.096 g, 0.428 mmol).The reaction mixture was warmed to 100° C. After 16 h, the reaction wascooled to rt. The reaction was filtered and the solid was rinsed withDMF. The filtrate was diluted with EtOAc, washed with water (2×), brine,dried over sodium sulfate, filtered and concentrated. Purification bynormal phase chromatography afforded Intermediate 4A (0.760 g, 63%), asa brown oil. MS (ESI) m/z: 225.0 (M-C₄H₈+H)⁺.

Intermediate 4. A solution of Intermediate 4A (0.048 g, 0.171 mmol) in50% TFA/DCM (2 mL) was stirred at rt. After 1h, the reaction wasconcentrated to give Intermediate 4 (0.038 g, 100% yield) as a yellowsolid. The material was used without further purification. MS (ESI) m/z:225.1 (M+H)⁺.

INTERMEDIATE 5 1-Amino-5,6,7,8-tetrahydroisoquinoline-6-carboxylic acid

The synthesis was described as Example 147, Part E in U.S. PatentApplication No. 2005/0282805 published Dec. 22, 2005.

INTERMEDIATE 6 2-Bromo-1-(2-(but-3-enyloxy)phenyl)ethanone

Intermediate 6A. 1-(2-But-3-enyloxy-phenyl)-ethanone: To a whitesuspension of potassium carbonate (15.2 g, 110 mmol) in acetone (29.4mL) was added 5-bromobut-1-ene (3.73 mL, 36.7 mmol) and1-(2-hydroxyphenyl)ethanone (4.42 mL, 36.7 mmol). The resultingoff-white suspension was warmed to reflux and stirred overnight. Thereaction was cooled to rt, filtered and the filtrate was concentrated.The residue was partitioned between water and EtOAc and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×20 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. Purification by normal phase chromatographygave 1.12 g (15%) of Intermediate 6A, as a dark purple oil. MS (ESI)m/z: 205.2 (M+H)⁺.

Intermediate 6. A suspension of Intermediate 6A (1.1153 g, 5.86 mmol)and copper (II) bromide (2.62 g, 11.73 mmol) in EtOAc (10.47 mL) waswarmed to reflux. After 1 h, the suspension was cooled to rt, filtered,and the filtrate was concentrated to give a greenish-brown residue. Thegreenish-brown residue was taken up in EtOAc (100 mL) and washed withwater (2×100 mL). The organic layer was then washed with brine, driedover Na₂SO₄, filtered, and concentrated. Purification by normal phasechromatography gave 0.773 g (44%) of Intermediate 6, as a yellow oil. MS(ESI) m/z: 271.1 (M+H)⁺.

INTERMEDIATE 7 Methyl 4-(2-bromoacetyl)-3-(but-3-enyloxy)phenylcarbamate

Intermediate 7A. 1-(4-Amino-2-(but-3-enyloxy)phenyl)ethanone: Asuspension of 1-(4-amino-2-hydroxyphenyl)ethanone (3 g, 19.85 mmol),4-bromobut-1-ene (6.04 mL, 59.5 mmol) and K₂CO₃ (16.46 g, 119 mmol) inacetone (30 mL) was heated in a sealed tube at 60° C. After 18 h,another 2 eq. of 4-bromobut-1-ene was added and the reaction was heatedat 60° C. for 18 h. This process was repeated one more time, and thereaction was cooled to rt, diluted with EtOAc, washed with water, brine,dried over sodium sulfate, filtered and concentrated. Purification bynormal phase chromatography afforded 1.055 g (14.24%) of Intermediate7A, as a yellow solid. MS (ESI) m/z: 206.0 (M+H)⁺.

Intermediate 7B. Methyl 4-acetyl-3-(but-3-enyloxy)phenylcarbamate: To acooled (0° C.), clear yellow solution of Intermediate 7A (1.055 g) inDCM (9.42 mL) and pyridine (0.252 mL, 3.11 mmol) was added dropwisemethyl chloroformate (0.230 mL, 2.97 mmol). The resulting yellowsuspension was stirred at 0° C. for 2 h. The reaction was partitionedbetween EtOAc/sat. sodium bicarbonate and the layers were separated. Theaqueous layer was extracted with EtOAc (1×). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated to give a yellow solid. The solid was purified bytrituration from DCM. The solid was collected via Buchner funnelfiltration and rinsed with DCM (3×2 mL), air-dried, and dried undervacuum to give 0.91 g of Intermediate 7B as a white solid. MS (ESI) m/z:264.0 (M+H)⁺.

Intermediate 7 was prepared following the procedure described inIntermediate 6, by replacing Intermediate 6A with Intermediate 7B. Thematerial was used without further purification. MS (ESI) m/z: 341.9(M+H)⁺ and 343.9 (M+2+H)⁺.

INTERMEDIATE 8 [3-Bromo-4-(2-bromo-acetyl)-phenyl]-carbamic acid methylester

Intermediate 8A 1-(4-Amino-2-bromophenyl)ethanone: (Caution, possibleexplosion hazard!) A clear, colorless solution of1-(2-bromo-4-fluorophenyl)ethanone (22.8 g, 0.105 mol) in DMSO (105 mL)and ammonium hydroxide (68.2 mL, 0.526 mol) was divided into nineteen20-mL microwave vials. The vials were sealed, microwaved at 150° C. for1.5 h, and then cooled to rt. All the reactions were combined,partitioned between DCM and water (400 mL) and the layers wereseparated. The aqueous layer was extracted with DCM (2×). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered, and concentrated to give 35g of Intermediate 8A as an orangeoil. The material was carried onto the next step without furtherpurification. MS (ESI) m/z: 212.4 (M+H)⁺ and 214.4 (M+2+H)⁺.

Intermediate 8 was prepared following the procedures described inIntermediate 7, by replacing Intermediate 7A with Intermediate 8A. MS(ESI) m/z: 352.1 (M+H)⁺ and 354.1 (M+2+H)⁺.

An Alternative Preparation of Intermediate 8 is Highlighted Below:

Alternative Intermediate 8A. 1-(4-Amino-2-bromophenyl)ethanone: To asolution of Intermediate 10C (19 g, 0.077 mol) in ethanol (400 mL) wasadded in portions tin(II) chloride (74 g, 0.39 mol). Following theaddition, the reaction was heated to reflux overnight. The reaction wasconcentrated and the residue was dissolved in 10% aq. sodium hydroxide(200 mL). The solution was extracted with ethyl acetate (2×200 mL). Thecombined organic layers were washed with brine and concentrated toafford an oil. Petroleum ether (25 mL) was added to give a suspension.The petroleum ether was decanted and the solid was suspended in 20%ethyl acetate/petroleum ether. The solid was collected to afford 14 g ofIntermediate 8A.

Alternative Intermediate 8B. (4-Acetyl-3-bromo-phenyl)-carbamic acidmethyl ester: To a cooled (10° C.) mixture of alternative Intermediate8A (14g, 0.065 mol) and Hunig's base (12.7 g, 0.098 mol) in dry dioxane(140 mL) was added dropwise methyl chloroformate (7.4 g, 0.078 m). After3 h, the reaction was quenched with water (100 mL) and then extractedwith ethyl acetate (2×150 mL). The combined organic layers were washedwith brine, dried over sodium sulfate, filtered, and concentrated.Purification by trituration from isopropanol provided 14 g of thealternative Intermediate 8B. MS (ESI) m/z: 271.7 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ: 2.50 (s, 3H), 3.71 (s, 3H), 7.53-7.56 (m, 1H), 7.78 (d,J=8.8 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 10.14 (s, 1H).

Alternative Intermediate 8. To a cooled (10° C.) solution of alternativeIntermediate 8B (90 g, 0.33 mol) in dry dioxane (900 mL) was added asolution of bromine (52.9 g, 0.33 mol) in dioxane (430 mL) dropwise over1h. After 2h, ice cold water (500 mL) was added and the reaction wasextracted with ethyl acetate (2×500 mL). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered, andconcentrated to afford 110 g of crude product. A suspension of the crudeproduct in ethanol (1 L) was warmed to 50° C. After a clear solutionformed, water (1.0 L) was added dropwise and the mixture was graduallycooled to 35° C. The precipitated solid was collected by filtration,washed with ethanol (200 mL), air-dried, and then dried at 50° C. undervacuum for 30 min to yield 70 g of alternative Intermediate 8.

INTERMEDIATE 9 Methyl 4-(2-bromoacetyl)-3-nitrophenylcarbamate

Intermediate 9A. Methyl 4-iodo-3-nitrophenylcarbamate: To a cooled (0°C.), yellow suspension of 4-iodo-3-nitroaniline (8.46 g, 32.0 mmol) inDCM (320 mL) and pyridine (2.85 mL, 35.2 mmol) was added dropwise methylchloroformate (2.61 mL, 33.6 mmol). The resulting clear, light yellowsolution was stirred at 0° C. After 1.5 h, the reaction was diluted withDCM, washed with sat. NaHCO₃, brine, dried over MgSO₄, filtered andconcentrated. The residue was dissolved in a minimal amount of DCM (˜100mL) and then hexane (600 mL) was added to give a yellow suspension. Thesuspension was filtered, and the solid was rinsed with hexane and thendried to give Intermediate 9A (10.3 g, 100%), as yellow solid. MS (ESI)m/z: 321.3 (M−H)⁻.

Intermediate 9B. Methyl 4-(1-ethoxyvinyl)-3-nitrophenylcarbamate: Asolution of Intermediate 9A (6 g, 18.63 mmol),tributyl(1-ethoxyvinyl)stannane (7.55 mL, 22.36 mmol), andbis(triphenylphosphine)palladium(II) chloride (0.654 g, 0.932 mmol) intoluene (37.3 mL) was heated at 110° C. After 2h, the reaction wascooled to rt. The reaction mixture was filtered through a 0.45 micronGMF, rinsing with EtOAc. The filtrate was concentrated. Purification bynormal phase chromatography gave Intermediate 9B (3.59 g, 72.4% yield),as a brown solid. MS (ESI) m/z: 267.4 (M+H)⁺.

Intermediate 9. To a slightly cloudy orange mixture of Intermediate 9B(3.59 g, 13.48 mmol) in THF (20 mL) and water (7 mL) was added NBS(2.400 g, 13.48 mmol). The resulting clear, yellow solution was stirredat rt for 20 min and then the reaction was partitioned betweenEtOAc/brine. The layers were separated and the organic layer washed withbrine, dried over Na₂SO₄, filtered, and concentrated to affordIntermediate 9 (4.28 g, 100% yield), as a yellow foam. This material wasused without further purification. MS (ESI) m/z: 317.3 (M+H)⁺, 319.3(M+2+H)⁺.

Alternatively, Intermediate 9B can be hydrolyzed with aqueous 1N HCl togive the methyl ketone which can then be brominated with copper (II)bromide according to the procedure described in Intermediate 6.

INTERMEDIATE 10 2-Bromo-1-(2-bromo-4-nitrophenyl)ethanone

Intermediate 10A. 2-Bromo-4-nitro-benzoic acid: To a warm (80° C.)solution of pyridine (500 mL) and water (1.0 L) was added4-nitro-2-bromo toluene (100 g, 0.46 mol). The resulting suspension wasstirred until it became a clear solution. Next, KMnO₄ (600 g, 3.8 mol)was added in portions over 1.5 h. The reaction was stirred overnight.The reaction mixture was cooled to RT and then 10% aq. sodium hydroxide(200 mL) was added. After 15 min, the reaction was filtered to removethe solid. The solid was rinsed with 10% aq. sodium hydroxide (5×100mL). The filtrate was extracted with MTBE (3×250 mL). The clear aqueouslayer was cooled to 10° C. and then it was acidified with concentratedHCl. The aqueous layer was extracted with MTBE (4×500 mL). The organiclayers were combined, dried over sodium sulfate, filtered andconcentrated to afford 72 g of Intermediate 10A. ¹H NMR (400 MHz,DMSO-d₆) δ: 7.96 (d, J=8 Hz, 1H), 8.28-8.48 (m, 1H), 8.49 (d, J=2.4 Hz,1H), 14.1 (br. s, 1H).

Intermediate 10B. 2-(2-Bromo-4-nitro-benzoyl)-malonic acid diethylester: To a solution of Intermediate 10A (50 g, 0.2 mol) in toluene (500mL) was added triethylamine (24.6 g, 0.24 mol). The reaction was cooledto 15° C. and ethyl chloroformate (24 g, 0.22 mol) was added. After 45min, the mixed anhydride solution was cooled to 0° C.

In a separate flask: To a suspension of Mg turnings (5.4 g) in dry ether(300 mL) was added ethanol (3.0 mL), carbon tetrachloride (2.0 mL), anddiethyl malonate (34 mL, 0.22 mol). The mixture was stirred at 40° C.for an hour to ensure that the magnesium dissolved completely. After thereaction became a clear solution, it was added to the cooled solution ofthe mixed anhydride. After 2 h, the reaction was quenched with 2Nsulfuric acid (200 mL) and then extracted with ethyl acetate (4×100 mL).The combined organic layers were dried over sodium sulfate, filtered andconcentrated to give 80 g of Intermediate 10B. This was used in the nextstep without further purification.

Intermediate 10C. 1-(2-Bromo-4-nitro-phenyl)-ethanone: A mixture ofIntermediate 10B (80 g, 0.2 mol) in acetic acid (400 mL) and sulfuricacid (400 mL) was stirred at 105° C. After 3h, the reaction was cooledto RT and then extracted with ethyl acetate (2×500 mL). The combinedorganic layers were washed with 20% aq. sodium hydroxide, dried oversodium sulfate, filtered and concentrated to give 43.0 g of Intermediate10C. ¹H NMR (400 MHz, CDCl₃) δ: 2.66 (s, 3H), 7.57 (d, J=8 Hz, 1H),8.21-8.24 (dd, 1H), 8.48 (d, J=2.0 Hz, 1H).

Intermediate 10. To a cooled (10° C.) solution of the Intermediate 10C(43 g, 0.17 mol) in dry dioxane (430 mL) was added a dropwise over 1.5 ha solution of bromine (31 g) in dioxane (430 mL). The reaction wasstirred for 30 min and then ice cold water (150 mL) was added. Thereaction was extracted with ethyl acetate (2×200 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated. Purification by normal phase chromatography(petroleum ether/ethyl acetate) gave 30 g of Intermediate 10. ¹H NMR(400 MHz, CDCl₃) δ 4.46 (s, 2H), 7.62 (d, J=8.4 Hz, 1H), 8.25-8.27 (dd,1H), 8.50 (d, J=2.4 Hz, 1H).

INTERMEDIATE 11 Methyl4-(2-bromoacetyl)-3-(pent-4-enyloxy)phenylcarbamate

This compound was prepared following the procedures described inIntermediate 7, by replacing 4-bromobut-1-ene with 5-bromopent-1-ene. MS(ESI) m/z: 355.9 (M+H)⁺, 357.9 (M+2+H)⁺.

INTERMEDIATE 122-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-5-nitro-phenylamine

To a flame-dried flask, equipped with a reflux condensor, containing2-bromo-5-nitroaniline (10.0 g, 46.1 mmol), bis(neopentylglycolato)diboron (13.01 g, 57.6 mmol), potassium acetate (13.57 g, 138mmol), and PdCl₂(dppf)-CH₂Cl₂ adduct (0.941 g, 1.152 mmol) was addedDMSO (132 mL). The resulting dark red-brown suspension was degassed withargon for 30 min. and then the reaction was warmed to 80° C. After 4 h,the reaction was stopped and cooled to rt. The reaction was pouredslowly into vigorously stirred ice-cold water (300 mL) to give a brownsuspension. After stirring for 10 min, the suspension was filtered tocollect the solid. The solid was rinsed with water (3×125 mL),air-dried, and then dried under a vacuum to give a brown solid.Purification by normal phase chromatography gave 4.36 g of Intermediate12 as an orange solid. MS (ESI) m/z: 183.1 (M-C₅H₈+H)⁺.

INTERMEDIATE 134-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-benzoicacid methyl ester

Intermediate 13A.4-Bromo-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-benzoic acidmethyl ester: To a solution of methyl 4-bromo-3-hydroxybenzoate (2.0 g,8.66 mmol) and 2-(2-bromoethyl)isoindoline-1,3-dione (2.419 g, 9.52mmol) in DMF (10 mL) was added NaH (0.866 g, 21.64 mmol) in smallportions at 0° C. The reaction was stirred under argon at 0° C. for 2 h.The reaction was warmed to 60° C. and stirred for 4 h. After cooling tort, the reaction mixture was diluted with EtOAc, washed with 1M HCl,saturated NaHCO₃ and brine. The organic phase was dried over MgSO₄,filtered and concentrated. Purification by normal phase chromatographygave Intermediate 13A (0.36 g, 10.3% yield) as a white solid. MS (ESI)m/z: 404.0/406.0 (M+H)⁺.

Intermediate 13 was prepared following the procedure described inIntermediate 12, by replacing 2-bromo-5-nitroaniline with Intermediate13A and running the reaction in acetonitrile at 90° C. MS (ESI) m/z:352.1 (M+H)⁺.

INTERMEDIATE 14[3-[(Benzyloxycarbonyl-methyl-amino)-methyl]-4-(2-bromo-acetyl)-phenyl]-carbamicacid methyl ester

Intermediate 14A. Benzyl 5-amino-2-bromobenzyl(methyl)carbamate: To amixture of benzyl 2-bromo-5-nitrobenzyl(methyl)carbamate (3.0 g, 7.91mmol) in MeOH (60 mL) was added ammonium chloride (2.116 g, 39.6 mmol)and zinc (2.59 g, 39.6 mmol) at 0° C. The reaction mixture was warmed upto rt and stirred under argon for 3 h. The solid was filtered off andthe solvent was removed to give Intermediate 14A (2.72 g, 98% yield) asa light tan solid. MS (ESI) m/z: 350.8 (M+H)⁺.

Intermediate 14 was prepared following the procedures described inIntermediate 9, by replacing 4-iodo-3-nitroaniline with Intermediate14A. MS (ESI) m/z: 449.0 (M+H)⁺.

INTERMEDIATE 15 (E)-3-(3-Chloro-2,6-difluoro-phenyl)-acrylic acid

Intermediate 15A. 3-Chloro-2,6-difluorobenzaldehyde: To a solution of(3-chloro-2,6-difluorophenyl)methanol (1.07 g, 5.99 mmol) in CH₂Cl₂ (20ml) was added Dess-Martin periodinane (3.05 g, 7.19 mmol). After 2h, thereaction was concentrated. Purification by normal phase chromatographygave Intermediate 15A (0.94 g, 89% yield), as a white solid. MS (ESI)m/z: 177.1 (M+H)⁺.

Intermediate 15B. (E)-tert-Butyl3-(3-chloro-2,6-difluorophenyl)acrylate: To a solution of Intermediate15A (0.94 g, 5.32 mmol) in THF (30 ml) were added tert-butyl2-(dimethoxyphosphoryl)acetate (1.194 g, 5.32 mmol) and KOtBu (0.896 g,7.99 mmol). After 2h, the reaction was diluted with EtOAc, washed withH₂O, brine, dried over MgSO₄, filtered and concentrated. Purification bynormal phase chromatography provided Intermediate 15B (0.866 g, 59.2%yield), as a clear colorless oil. MS (ESI) m/z: 219.2 (M-^(t)Bu+H)⁺.

Intermediate 15. To a solution of Intermediate 15B (0.866 g, 3.15 mmol)in DCM (7.0 ml) was added TFA (3.0 mL, 38.9 mmol). After 1.5 h, thereaction was concentrated and the residue was dried in vacuo to giveIntermediate 15 (0.689 g, 100% yield) as an off-white solid. MS (ESI)m/z: 219.1 (M+H)⁺.

INTERMEDIATE 17 2-Bromo-1-(2-bromo-4-fluoro-phenyl)-ethanone

The synthesis was described as Method A-1, Page 92 in PCT InternationalApplication No. WO 2005/014566 published Feb. 17, 2005.

INTERMEDIATE 18 (E)-3-(6-Acetyl-3-chloro-2-fluoro-phenyl)-acrylic acid

Intermediate 18A. 2-Bromo-4-chloro-3-fluorobenzoic acid: To a cooled(−78° C.) solution of DIEA (4.9 mL, 48 mmol) in THF was added dropwisen-BuLi (132 mL, 2.3 eq, 2.5 M solution). The mixture was stirred at −30°C. for 30 min. Again the reaction mixture was cooled to −78° C., and asolution of 4-chloro-3-fluorobenzoic acid (25 g, 143 mmol) in THF wasadded over 1 h. The reaction was stirred at −78° C. overnight. The nextday a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (87 g, 267 mmol)in THF was added and the reaction was stirred at −78° C. for further 2 hand then RT for 4 h. The reaction mixture was quenched with water, thelayers were separated, and the aqueous layer washed with Et₂O. Theaqueous layer was acidified with 1.5N HCl and then extracted in EtOAc(2×200 mL). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated to afford Intermediate 18A (30 g,83.3%). MS (ESI) m/z: 252.6 (M−H)⁺.

Intermediate 18B. Diethyl 2-((2-bromo-4-chloro-3-fluorophenyl)(hydroxy)methylene)malonate: To a suspension of Intermediate 18A (14.6g, 57 mmol) in DCM (200 mL) was added thionyl chloride (6.6 mL, 88mmol). The mixture was stirred at reflux for 3 h. The solvent wasremoved and the residue was dried in vacuum to give the acid chloride asa light brown solid.

To a cooled (0° C.) suspension of sodium hydride (3.66 g (60%), 91.5mmol) in THF was added a solution of diethyl malonate (0.612 g, 3.82mmol) in THF (5 mL). After 10 min, a solution of the acid chloride (16.4g, 60 mmol) in THF (160 mL) was added slowly. Following the addition,the reaction was warmed to RT. After 30 min, the solvent was removed andthe residue was treated with cold (0° C.) 1.2 M HCl (150 mL). Themixture was extracted with EtOAc (3×250 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated togive Intermediate 18B (20 g, 87%) as a solid. MS (ESI) m/z: 395/397(M+H)⁺.

Intermediate 18C. 1-(2-Bromo-4-chloro-3-fluorophenyl)ethanone: Asolution of Intermediate 18B (18.6 g, 47 mmol) in acetic acid (200 mL),H₂O (150 mL) and H₂SO₄ (2.0 mL) was stirred at 110° C. for 4 h. Most ofthe solvent was removed and the residue was diluted with EtOAc (400 mL),washed with water (5×20 mL), saturated NaHCO₃, 1N NaOH, and brine. Thesolvent was removed to give Intermediate 18C (10 g, 84%) as a lowmelting solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.42 (q, J=6.8, 6.4 Hz, 1H), 7.24 (q, J=6.4, 5.2 Hz, 1 H), 2.5 (s, 3H).

Intermediate 18D. (E)-tert-Butyl3-(6-acetyl-3-chloro-2-fluorophenyl)acrylate: To the mixture ofIntermediate 18C (50 g, 198 mmol), tert-butyl acrylate (50.9 g, 397mmol) and TEA (55 mL, 397 mmol) in DMF (500 mL) was added Pd(OAc)₂ (8.9g, 39.7 mmol). The resulting mixture was stirred at 90° C. overnight.The reaction was cooled to RT, filtered, and the filtrate wasconcentrated. Purification by normal phase chromatography gaveIntermediate 18D (30 g, 50.8%) as a light yellow solid. MS (ESI) m/z:242.7 (M+H)⁺.

Intermediate 18. A solution of Intermediate 18D (25 g, 84 mmol) in DCM(330 mL) and TFA (330 mL) was stirred at RT. After 1.5 h, the solventwas concentrated to give Intermediate 18 (19.5 g, 97.0) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ: 12.69 (bs, 1 H), 7.80-7.76 (m, 2 H),7.62 (d, J=12.1 Hz, 1 H), 6.30 (dd, J=2.4, 2.0 Hz, 1 H), 2.6 (s, 3H). MS(ESI) m/z: 241 (M−H)⁺.

INTERMEDIATE 19 (E)-3-(5-Chloro-2-(difluoromethyl)phenyl)acrylic acid

Intermediate 19A. 2-Bromo-4-chloro-1-(difluoromethyl)benzene: To asolution of 2-bromo-4-chlorobenzaldehyde (1 g, 4.56 mmol) in DCM (15 mL)was added DAST (0.903 mL, 6.83 mmol) at 0° C. The reaction was allowedto warm to rt and stir overnight. The reaction mixture was diluted withEtOAc, washed with sat NaHCO₃ and brine. The organic phase was driedover magnesium sulfate, filtered and concentrated to give Intermediate19A (0.88g. 80% yield) as a clear oil. MS (ESI) m/z: 261.2 (M+Na)⁺.

Intermediate 19B. (E)-tert-Butyl3-(5-chloro-2-(difluoromethyl)phenyl)acrylate: To a solution ofIntermediate 19A (0.88 g, 3.64 mmol) in DMF (10 mL) was added tert-butylacrylate (1.401 g, 10.93 mmol), TEA (1.270 mL, 9.11 mmol) and palladiumacetate (0.082 g, 0.364 mmol). The reaction was warmed to 90° C. After5h, the reaction was cooled to rt and then filtered to remove the solid.The filtrate was diluted with EtOAc, washed with 1M HCl, sat NaHCO₃ andbrine. The organic phase was dried over magnesium sulfate, filtered andconcentrated. Purification by normal phase chromatography gaveIntermediate 19B (232 mg, 22% yield) as a tan oil. MS (ESI) m/z: 233.1(M-tBu)⁺.

Intermediate 19. A solution of Intermediate 19B (232 mg, 0.804 mmol) inDCM (2.0 mL) was added TFA (2.0 mL, 26.0 mmol). The reaction was stirredunder argon at rt. After 1h, the solvent was removed and the residue wasdried to give Intermediate 19 (191 mg, 100% yield) as tan solid. ¹H NMR(400 MHz, CD₃OD) δ 7.99 (dt, J=15.8, 1.5 Hz, 1H), 7.83 (s, 1H), 7.60 (d,J=8.3 Hz, 1H), 7.55-7.48 (m, 1H), 7.01 (t, J=54.6 Hz, 1H), 6.51 (d,J=15.8 Hz, 1H). ¹⁹F NMR (376 MHz, CD₃OD) □ δ −111.67 (s, 2F). MS (ESI)m/z: 233.1 (M+H)⁺.

INTERMEDIATE 20 (E)-3-(5-Chloro-2-(1H-1,2,4-triazol-1-yl)phenyl)acrylicacid

Intermediate 20A. 5-Chloro-2-(1H-1,2,4-triazol-1-yl)benzaldehyde: Amixture of 5-chloro-2-fluorobenzaldehyde (0.634 g, 4 mmol),1H-1,2,4-triazole (0.290 g, 4.20 mmol), and cesium carbonate (1.564 g,4.80 mmol) in DMF (6 mL) was stirred at 50° C. After 20 h, the reactionwas cooled to RT, partitioned between water and EtOAc and the layerswere separated. The organic layer was washed with water, brine, driedover Na₂SO₄, filtered and concentrated. The residue was suspended in DCM(5 mL) and then it was filtered. The solid was washed with hexane,air-dried, and dried under vacuum to give 0.22 g (26.5%) of Intermediate20A, as a yellow solid. MS (ESI) m/z: 208.1 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ: 7.48 (d, J=8.2 Hz, 1 H), 7.72 (dd, J=2.2 Hz, 8.2 Hz, 1 H),8.06 (d, J=2.2 Hz, 1 H), 8.20 (s, 1 H), 8.48 (s, 1 H), 9.99 (s, 1 H).

Intermediate 20B. (E)-tert-Butyl3-(5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl)acrylate: To a suspension ofNaH (60%, 0.100 g, 2.495 mmol) in THF (4 mL) was added dropwisetert-butyl 2-(dimethoxyphosphoryl)acetate (0.530 mL, 2.67 mmol). Thecloudy reaction mixture was stirred at RT for 45 min and then cooled to0° C. Next a solution of Intermediate 20A (0.37 g, 1.78 mmol) in THF (14mL) was added. The reaction mixture turned orange. After 30 min, thereaction was quenched with saturated NH₄Cl and then the reaction wasdiluted with EtOAc and water. The layers were separated and the organiclayer was washed with brine, dried over Na₂SO₄, filtered andconcentrated. Purification by normal phase chromatography afforded 0.178g (26%) of Intermediate 20B, as a yellow gum. MS (ESI) m/z: 306.3(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.49 (s, 9 H), 6.38 (d, J=15.9 Hz,1 H), 7.34-7.42 (m, 2 H), 7.48 (dd, J=8.3, 2.2 Hz, 1 H), 7.73 (d, J=2.2Hz, 1 H), 8.17 (s, 1 H), 8.29 (s, 1 H).

Intermediate 20. To a solution of Intermediate 20B (0.178 g, 0.582 mmol)in DCM (1 ml) was added TFA (1 ml, 12.98 mmol). The reaction mixture wasstirred at rt for 1 h and then it was concentrated to dryness. MeOH (3mL) was added to give a white suspension. The solid was collected byfiltration, rinsing with a small amount of methanol. The solid wasair-dried and dried under vacuum to give 0.076 g (52%) of Intermediate20 as a white solid. MS (ESI) m/z: 250.1 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 6.65 (d, 15.9 Hz, 1 H), 7.21 (d, 15.9 Hz, 1 H), 7.60 (d,J=8.2 Hz, 1 H), 7.68 (dd, J=2.2 Hz, 8.2 Hz, 1 H), 8.16 (d, J=2.2 Hz, 1H), 8.32 (s, 1 H), 8.93 (s, 1 H), 12.64 (s, 1 H).

INTERMEDIATE 21 (E)-3-(5-Chloro-2-(4H-1,2,4-triazol-4-yl)phenyl)acrylicacid

Intermediate 21A. 4-(4-Chloro-2-iodophenyl)-4H-1,2,4-triazole: To asuspension of 4-chloro-2-iodoaniline (0.760 g, 3 mmol) andN′-formylformohydrazide (0.793 g, 9 mmol) in pyridine (12 ml) was addeddropwise chlorotrimethylsilane (5.71 ml, 45 mmol) followed by TEA (2.84ml, 20.4 mmol). The reaction mixture was heated at 100° C. After 4 h,the reaction was cooled to rt and the reaction was concentrated to givea solid. The solid was suspended in water and the solid was collected byfiltration, washing with water. The solid was air-dried and dried undervacuum to give 0.8 g as an off-white solid. Purification by normal phasechromatography afforded 0.59 g (64%) of Intermediate 21A, as a whitesolid. MS (ESI) m/z: 306.1 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.56(d, J=8.2 Hz, 1 H), 7.67 (dd, J=2.2 Hz, 8.2 Hz, 1 H), 8.17 (d, J=2.2 Hz,1 H), 8.78 (s, 2 H).

Intermediate 21B. (E)-tert-Butyl3-(5-chloro-2-(4H-1,2,4-triazol-4-yl)phenyl)acrylate: To a degassedsolution of Intermediate 21A (0.48 g, 1.571 mmol), tributylamine (0.749mL, 3.14 mmol), and tert-butyl acrylate (1.151 mL, 7.86 mmol) in DMF(7.86 mL) was added palladium on carbon (10% w/w, 0.167 g, 0.157 mmol)and palladium(II) acetate (0.035 g, 0.157 mmol). The reaction was heatedat 100° C. for 18 h. Additional tert-butyl acrylate (1.151 mL, 7.86mmol) and palladium(II) acetate (0.035 g, 0.157 mmol) was added and thereaction was stirred at 100° C. for another 48 h. The reaction wascooled to RT, filtered through a 0.45 μm GMF, and rinsed with EtOAc. Thefiltrate was diluted with EtOAc, washed with water, brine, dried overNa₂SO₄, filtered and concentrated. Purification by normal phasechromatography followed by reverse phase chromatography gave 0.122 g(25%) of Intermediate 21B, as a white solid. ¹H NMR (500 MHz, CD₃OD) δppm 1.47 (s, 9 H), 6.51 (d, J=16.0 Hz, 1 H), 7.12 (d, J=15.7 Hz, 1 H),7.52 (d, J=8.5 Hz, 1 H), 7.62 (dd, J=8.5, 2.2 Hz, 1 H), 7.97 (d, J=2.2Hz, 1 H), 8.86 (s, 2 H).

Intermediate 21. To the solution of Intermediate 21B (0.122 g, 0.399mmol) in DCM (0.5 mL) was added TFA (0.5 mL, 6.49 mmol). The reactionwas stirred at rt for 2 h, then it was concentrated to afford 0.100 g(100%) of Intermediate 21, as a white solid. MS (ESI) m/z: 249.9 (M+H)⁺.

INTERMEDIATE 22 4-(N-(tert-Butoxycarbonyl)carbamimidoyl)benzoic acid, 2NaOH salt

Intermediate 22A. Methyl 4-(N-hydroxycarbamimidoyl)benzoate: To asolution of methyl 4-cyanobenzoate (1.003 g, 6.22 mmol) in MeOH (15 mL)was added hydroxylamine hydrochloride (2.162 g, 31.1 mmol) and TEA (4.34mL, 31.1 mmol). The reaction was stirred at rt for 24 h, then thereaction was concentrated to give a white solid. Water and DCM wereadded to give a suspension. The suspension was filtered and the solidwas rinsed with water and then air-dried to give 1.14 g (94%) ofIntermediate 22A, as a white solid. MS (ESI) m/z: 195.0 (M+H)⁺. ¹H NMR(500 MHz, CD₃OD) δ ppm 3.91 (s, 3 H), 7.74-7.77 (m, 2 H), 8.01-8.04 (m,2 H). The material was carried onto the next step without furtherpurification.

Intermediate 22B. Methyl 4-carbamimidoylbenzoate, 1 acetic acid salt: Toa solution of Intermediate 22A (1.14 g, 5.87 mmol) in acetic acid (5 mL)was added acetic anhydride (2 mL, 21.20 mmol). The reaction turned to awhite gel. After 10 min, MeOH (50 mL) was added followed by palladium oncarbon (10% w/w, 0.625 g, 0.587 mmol). Hydrogen gas was bubbled throughthe reaction mixture for a few minutes, then the reaction was stirredunder a H₂-balloon. After 24 h, the reaction was filtered through a 0.45μm GMF rinsing with MeOH. The filtrate was concentrated to give 1.32 g(94%) of Intermediate 22B as a white solid. MS (ESI) m/z: 179.0 (M+H)⁺.¹H NMR (400 MHz, CD₃OD) δ ppm 1.90 (s, 3 H), 3.96 (s, 3 H), 7.89 (d,J=8.8 Hz, 2 H), 8.22 (d, J=8.8 Hz, 2 H).

Intermediate 22C. Methyl4-(N-(tert-butoxycarbonyl)carbamimidoyl)benzoate: To a white suspensionof Intermediate 22B (1.82 g, 7.64 mmol) in DCM (102 mL) was addeddi-tert-butyl dicarbonate (2.452 g, 11.24 mmol) and TEA (4.27 mL, 30.6mmol). The reaction mixture was stirred at rt. Overtime, the reactionbecame a clear solution. After 72 h, additional di-tert-butyldicarbonate (0.4 eq, 0.879 g) was added, and the reaction was stirred atrt. After an additional 24 h, the reaction was concentrated.Purification by normal phase chromatography afforded 0.84 g (30%) ofIntermediate 22C as a white solid. MS (ESI) m/z: 277.3 (M−H)⁻. ¹H NMR(500 MHz, CD₃OD) δ ppm 1.52 (s, 9 H), 3.93 (s, 3 H), 7.86-7.91 (m, 2 H),8.07-8.10 (m, 2 H).

Intermediate 22. To a solution of Intermediate 22C (0.84 g, 3.02 mmol)in MeOH (15.09 mL) was added 1N NaOH (6.04 mL, 6.04 mmol) to give acloudy white mixture. Additional MeOH (15.09 mL) was added and theresulting clear solution was stirred at rt. After 24 h, the reaction wasconcentrated to give 0.895 g (86%) of Intermediate 22, as a white solid.MS (ESI) m/z: 265.3 (M+H)⁺. The material was used in the next stepwithout further purification.

INTERMEDIATE 23 (E)-3-(5-Chloro-2-1,2,3-triazol-1-yl-phenyl)-acrylicacid

Intermediate 23A. 5-Chloro-2-1,2,3-triazol-1-yl-benzaldehyde andIntermediate 23B. 5-Chloro-2-1,2,3-triazol-2-yl-benzaldehyde: To asolution of 5-chloro-2-fluorobenzaldehyde (1 g, 6.31 mmol) in DMF (12.6mL) was added 1H-1,2,3-triazole (0.365 ml, 6.31 mmol) and Cs₂CO₃ (4.11g, 12.61 mmol). The reaction was stirred at rt for 18 h. Water was addedto the reaction, and the resulting suspension was acidified with 1N HClto pH<3, and then the reaction was filtered. The filtrate was extractedwith EtOAc (3×). The organic layers were combined and washed with water,brine, dried over Na₂SO₄, filtered and concentrated. Trituration withDCM/hexane gave 0.35 g as a mixture of Intermediate 23A and Intermediate23B as a yellow solid. The material was used in the next step withoutfurther purification.

Intermediate 23C. (E)-3-(5-Chloro-2-1,2,3-triazol-1-yl-phenyl)-acrylicacid tert-butyl ester and Intermediate 23D.(E)-3-(5-Chloro-2-1,2,3-triazol-2-yl-phenyl)-acrylic acid tert-butylester: The title compounds were prepared according to the proceduredescribed in Intermediate 20B, by replacing Intermediate 20A with amixture of Intermediate 23A and Intermediate 23B. The triazoleregioisomers were separated by normal phase chromatography which gave0.147 g (28.5%) of Intermediate 23C. MS (ESI) m/z: 306.1 (M+H)⁺. ¹H NMR(500 MHz, CDCl₃) δ ppm 1.48 (s, 9 H), 6.36 (d, J=16.0 Hz, 1 H), 7.21 (d,J=16.0 Hz, 1 H), 7.44 (d, J=8.5 Hz, 1 H), 7.48-7.52 (dd, J=8.5, 2.2 Hz,1 H), 7.74 (d, J=2.2 Hz, 1 H), 7.79 (d, J=1.1 Hz, 1 H), 7.89 (d, J=1.1Hz, 1 H).

Intermediate 23. The title compound was prepared according to theprocedure described in Intermediate 20, by replacing Intermediate 20Bwith Intermediate 23C. MS (ESI) m/z: 250.0 (M+H)⁺. ¹H NMR (500 MHz,CD₃OD) δ ppm 6.51 (d, J=15.7 Hz, 1 H), 7.22 (d, J=16.0 Hz, 1 H), 7.53(d, J=8.5 Hz, 1 H), 7.63 (dd, J=8.4, 2.3 Hz, 1 H), 7.96 (d, J=0.83 Hz, 1H), 8.00 (d, J=2.2 Hz, 1 H), 8.30 (d, J=0.83 Hz, 1 H).

INTERMEDIATE 24 (E)-3-(5-Chloro-2-difluoromethoxy-phenyl)-acrylic acid

Intermediate 24A. (E)-3-(5-Chloro-2-difluoromethoxy-phenyl)-acrylic acidtert-butyl ester: To a cooled (0° C.) solution of potassiumtert-butoxide (0.407 g, 3.63 mmol) in THF (10 mL) was added tert-butyl2-(dimethoxyphosphoryl)acetate (0.528 mL, 2.66 mmol) and5-chloro-2-(difluoromethoxy)benzaldehyde (0.50g, 2.420 mmol). Thereaction was allowed to warm to RT. After 4h, the reaction was quenchedwith the addition of sat. ammonium chloride. The reaction was dilutedwith EtOAc, washed with sat. ammonium chloride, sat NaHCO₃ and brine.The organic layer was dried over sodium sulfate, filtered andconcentrated. Purification by normal phase chromatography gave 550 mg(74%) of Intermediate 24A as a white solid. ¹H NMR (400 MHz, CDCl₃) δppm 7.77 (1 H, d, J=16.31 Hz), 7.58 (1 H, d, J=2.51 Hz), 7.31 (1 H, dd,J=8.66, 2.64 Hz), 7.12 (1 H, d, J=8.78 Hz), 6.52 (1 H, t, J=72.78 Hz)6.40 (1 H, d, J=16.31 Hz), 1.53 (9 H, s). ¹⁹F NMR (376 MHz, CDCl₃) δ ppm−81.11. MS (ESI) m/z: 327.0 (M+Na)⁺.

Intermediate 24. To a solution of Intermediate 24A (458 mg, 1.503 mmol)in DCM (4.0 mL) was added TFA (2.0 mL, 26.0 mmol). The reaction wasstirred under argon at RT for 1h. The solvent was removed to giveIntermediate 24 as a white solid. MS (ESI) m/z: 249.0 (M+H)⁺.

INTERMEDIATE 25 3-(5-Chloro-2-tetrazol-1-yl-phenyl)-propionic acid

The synthesis was described as Example 63A in PCT InternationalApplication No. WO 2007/070826 published Jun. 21, 2007.

INTERMEDIATE 26 3-(3-Chlorophenyl)-4,5-dihydroisoxazole-5-carboxylicacid

Intermediate 26 was obtained via the procedure described in U.S. Pat.No. 4,889,551 A1 (1989).

INTERMEDIATE 27 3-(3-Chlorophenyl)isoxazole-5-carboxylic acid

Intermediate 27 was obtained via the procedure described by Gruenanger,F., Gazz. Chim. Ital., 89:598-609 (1959).

INTERMEDIATE 28 1-(3-Chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

Intermediate 28 was obtained via the procedure described by Sader Al, B.H. et al., Tetrahedron Letters, 4661-4664 (1985).

INTERMEDIATE 29 4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-benzoicacid

Intermediate 29A. 4-Cyano-2,6-difluoro-benzoic acid: To a cooled (−78°C.) clear, colorless solution of 3,5-difluorobenzonitrile (1 g, 7.19mmol) in THF (28.8 mL) was added dropwise 1.6M n-butyllithium in hexane(4.49 ml, 7.19 mmol) to give a red-orange solution. After 45 min, carbondioxide (sublimation of dry ice passing through a drierite tower) wasbubbled through the reaction to eventually give a thick off-whitesuspension. After 25 min, the reaction was quenched with 1M HCl (aq) andthe reaction was allowed to warm to RT. The reaction was extracted withEtOAc(2×). The organic layers were combined, washed with brine, driedover Na₂SO₄, filtered and concentrated to a white residue. The cruderesidue was partitioned between EtOAc and 1M NaOH (aq) and the layerswere separated. The organic layer was extracted with 1N NaOH (aq) (2×).The aqueous layers were combined and then washed with EtOAc (2×). Theaqueous layer was then acidified to pH ˜2 to give a cloudy whitesuspension. The aqueous layer was then extracted with EtOAc (2×). Theorganic layers were combined, washed with brine, dried over Na₂SO₄,filtered and concentrated to a give 922.5 mg (65.3%) of Intermediate 29Aas a white solid. MS (ESI) m/z: 184.0 (M+H)⁺.

Intermediate 29B. 4-Aminomethyl-2,6-difluoro-benzoic acid: A blacksuspension of Intermediate 29A (922.5 mg, 5.04 mmol) and Pd/C (268 mg,0.126 mmol) in EtOH (50.4 mL) was degassed with hydrogen (balloon) forseveral minutes. The reaction was stirred under hydrogen atmosphere for24 h. The reaction was filtered through CELITE® eluting with 1M HCl (aq)and MeOH. The filtrate was concentrated to a pale yellow solid. Thesolid was dissolved in (1:1) 1N HCl and EtOAc and the layers wereseparated. The aqueous layer was neutralized to pH 7 and extracted with15% isopropanol/chloroform. The aqueous layer still contained someproduct, so both the organic and aqueous layers were concentrated andcombined to give Intermediate 29B as an off-white solid. MS (ESI) m/z:188.0 (M+H)⁺. The product was used as is without further purification.

Intermediate 29. To a suspension of Intermediate 29B (943 mg, 4.22 mmol)in DCM (14.1 mL) was added triethylamine (2.351 mL, 16.87 mmol) followedby BOC₂O (1.077 mL, 4.64 mmol). DMF (5 mL) was added to facilitatemixing. After stirring for 1.5 h, the slightly purple suspension wasdiluted with water and DCM and the layers were separated. The aqueouslayer was neutralized to pH-7 using 1N HCl (aq) and then extracted withEtOAc (2×). The organic layers were combined, washed with brine, driedover Na₂SO₄, filtered and concentrated to give a viscous, pink oil.Purification by normal phase chromatography (0-10% DCM:MeOH) gave 803.2mg (55.0%) of Intermediate 29, as a clear oil. MS (ESI) m/z: 232.2(M-C₄H₈+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ: 1.46 (s, 9 H), 4.24 (s, 2 H),6.95 (d, J=9.3 Hz, 2 H).

INTERMEDIATE 30 4,6-Difluoro-1-methyl-1H-benzo[d]imidazole-5-carboxylic

Intermediate 30A. 3,5-Difluoro-N-methyl-2-nitroaniline: To a solution of1,3,5-trifluoro-2-nitrobenzene (1.0 g, 5.65 mmol) and methanamine (8.47mL, 16.94 mmol) in MeOH (10 mL) was stirred for 4 h at 80° C. Reactionmixture was concentrated in vacuo, yielding oil, which was subjected tothe following reaction w/o any further purification. MS (ESI) m/z: 189.2(M+H)⁺.

Intermediate 30B. 4,6-Difluoro-1-methyl-1H-benzo[d]imidazole: Solutionof Intermediate 30A (1.063 g, 5.65 mmol) in formic acid (5 mL) washeated at 80° C. for 12h. Rxn mixture after concentration was diluted inEtOAc (100 mL) and washed with 1N aq NaOH. Organic solution was driedover Na₂SO₄ and concentrated in vacuo, yielding oily mixture. It waspurified on normal phase column chromatography to yield Intermediate 30B(0.39 g, 41.1%).

Intermediate 30. (Reference: WO 2009/083526) To a solution ofIntermediate 30B (227 mg, 1.35 mmol) in THF (10 mL) was added BuLi (0.74mL, 1.485 mmol) dropwise and the resulting solution was stirred for 0.5hat −78° C. To the solution was added bromotrimethylsilane (0.175 mL,1.350 mmol) dropwise and solution was stirred for 15 min. To thesolution was added sec-butyllithium (1.298 mL, 1.688 mmol) dropwise andsolution was stirred for 0.5h. The solution was then poured into THFsolution of dry ice (2 pieces). The solution was stirred for 1h at −78°C. The reaction was then quenched by adding 1N HCl and the reaction waswarmed to RT. The reaction was concentrated and then it was purified byreverse phase chromatography which gave Intermediate 30 (121 mg, 41.0%).¹H NMR (400 MHz, CD₃OD) δ ppm 8.80 (s, 1 H), 7.51 (d, J=9.0 Hz, 1 H),3.99 (s, 3 H). MS(ESI) m/z: 213.0 (M+H)⁺.

INTERMEDIATE 31 4,6-Difluoro-1-methyl-1H-indazole-5-carboxylic acid

Intermediate 31A. (E)-1-Methyl-2-(2,4,6-trifluorobenzylidene)hydrazine:A solution of monomethyl hydrazine (2.158 g, 46.8 mmol) and2,4,6-trifluorobenzaldehyde (2.5g, 15.6 mmol) in THF (20 mL) was stirredat RT for 5h. The reaction mixture was concentrated in vacuo, yieldingoily residue, which was subjected to the following reaction w/o furtherpurification. MS (ESI) m/z: 189.4 (M+H)⁺.

Intermediate 31B. 4,6-Difluoro-1-methyl-1H-indazole: A solution ofIntermediate 31A (8.84 g, 47 mmol) in DMF (5 mL) and pyridine (5.00 mL)was stirred at 90° C. for 12h. The reaction mixture was concentrated invacuo, yielding an oily mixture, which was purified on normal phasechromatography to provide Intermediate 31B (2.3 g, 29.1%). ¹H NMR (400MHz, CDCl₃) δ ppm 7.94 (s, 1 H), 6.78 (d, J=8.5 Hz, 1 H), 6.55 (td,J=9.7, 1.8 Hz, 1 H), 3.95 (s, 3 H). MS (ESI) m/z: 169.0 (M+H)⁺.

Intermediate 31. To a solution of Intermediate 31B (250 mg, 1.48 mmol)in THF (15 mL) was added LDA (0.89 μL, 1.78 mmol) in several portionsand the resulting dark solution was stirred for 0.5h at −78° C. To thesolution was added a few pieces of dry ice. The resulting solution wasstirred at −78° C. for 0.5h and at 25° C. for 0.5h. It was diluted withEtOAc (40 mL) and washed with 1N HCl. Organic solution was dried overMgSO₄ and concentrated in vacuo, yielding oil, which was then purifiedon reverse phase chromatography to yield Intermediate 31 (0.26g, 82%).¹H NMR (400 MHz, CD₃OD) δ ppm 8.15 (s, 1 H), 7.27 (d, J=10.0 Hz, 1 H),4.04 (s, 3 H). MS (ESI) m/z: 212.9 (M+H)⁺.

INTERMEDIATE 32 4,6-Difluoro-1-methyl-1H-indole-5-carboxylic acid

Intermediate 32A. 4,6-Difluoro-1-methyl-1H-indole: The synthesis isdescribed in WO 2009/050235.

Intermediate 32. In a flame-dried 25 ml RBF, diisopropylamine (0.352 ml,2.51 mmol) in 10 ml dry THF was cooled down to 0° C. under Ar,butyllithium (1.6M in Hexane) (1.571 ml, 2.51 mmol) was added, stirredat 0° C. for 30 mins, before cooling down to −78° C. Intermediate 32A(382 mg, 2.285 mmol) in 2 ml dry THF was added dropwise, stirred at −78°C. for 1 hrs, before dry ice was added to the reaction. The reaction wasstirred at −78° C. for 30 mins and then warmed up to rt and stirred atrt overnight. The reaction was concentrated, diluted with EtOAc, washedwith H₂O, washed again with EtOAc. The aqueous layer was acidified with1N HCl, white precipitate formed immediately. It was extracted withEtOAc twice. EtOAc layers washed with brine, dried over MgSO₄, filteredoff solid, concentrated to give Intermediate 32 as a pale yellow solid(177 mg, 38%). MS (ESI) m/z: 212.1 (M+H)⁺.

INTERMEDIATE 33 4-Amino-2,6-difluoro-benzoic acid

Intermediate 33A. 4-Bromo-2,6-difluorobenzoic acid methyl ester: To asolution of 4-bromo-2,6-difluorobenzoic acid (1.00 g, 4.22 mmol) in 30mL methanol was added TMS-Cl (1.1 ml, 8.61 mmol), and the mixture washeated at 60° C. under N₂ over night. An additional 1 mL TMS-Cl wasadded and heating continued at 60° C. for an additional 4 h. Reactionmixture was cooled to RT and diluted with aq. NaOH, then extracted withEtOAc. The combined organic extracts were washed with dilute aq. NaOH toremove unreacted starting material, then dried over Na₂SO₄, filtered andevaporated to obtain Intermediate 33A as a pale pink solid (0.86g, 81%)MS (ESI) m/z: 251.05 (M+H)⁺.

Intermediate 33B. 4-(Benzhydrylidene-amino)-2,6-difluoro-benzoic acidmethyl ester: Intermediate 33A (0.600 g, 2.390 mmol) and cesiumcarbonate (1.324 g, 4.06 mmol) were weighed into a 50 mL 3-necked rbfand flushed with N₂. Palladium(II) acetate (10.73 mg, 0.048 mmol) andrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.045 g, 0.072 mmol)were added, followed by 7.5 mL toluene. Benzophenone imine (0.521 ml,3.11 mmol) was then added to the above mixture, and the reaction washeated with stirring at 100° C. overnight. The reaction mixture wasdiluted with ˜50 mL Et₂O, and filtered. The filtrate was evaporated andthe residue was purified by flash chromatography to provide Intermediate33B as a yellow oil which was used without further purification in thenext step. MS (ESI) m/z: 352.2 (M+H)⁺.

Intermediate 33. Intermediate 33B (0.840 g, 2.39 mmol) was dissolved inMeOH (16 mL), and hydroxylamine hydrochloride (0.332 g, 4.78 mmol) andsodium acetate (0.490 g, 5.98 mmol) were added. The mixture was stirredfor ˜1h and then diluted with water and extracted with EtOAc. Thecombined organic layers were washed with water and brine, then driedover Na₂SO₄, filtered and evaporated. The crude product was dissolved inEtOH (˜12 mL) and 1M NaOH (6 mL, 6.0 mmol) was added. The mixture wasstirred for 3 days at room temperature. Reaction mixture was neutralizedwith 1M HCl and then evaporated to remove ethanol. The residue wasredissolved in MeOH, filtered and evaporated (2×) to remove the bulk ofthe inorganic salts. The filtrate was evaporated and the residue waspurified by reverse phase HPLC to provide Intermediate 33 (0.36g, 88%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 5.99 (s, 2 H) 6.10 (d,J=10.99 Hz, 2 H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −111.82 (s, 2 F).

INTERMEDIATE 344,6-Difluoro-1-(2-fluoro-ethyl)-1H-benzoimidazole-5-carboxylic acid

Intermediate 34 was prepared following the procedures described inIntermediate 30, by replacing methylamine with 2-fluoroethanamine, HCl.MS (ESI) m/z: 245.1 (M+H)⁺.

INTERMEDIATE 357-Chloro-4,6-difluoro-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid

Intermediate 35A. 2-Chloro-3,5-difluoro-N-methyl-6-nitroaniline:Solution of Intermediate 30A (1.1 g, 5.85 mmol) and NCS (0.781 g, 5.85mmol) in acetonitrile (25 mL) was stirred for 12h at 70° C. The reactionmixture was concentrated in vacuo, yielding yellow solid, which wasredissolved in EtOAc and washed with aq. NaHCO₃ and brine. Concentrationof organic solution provided oily residue, which was purified on normalphase chromatography to provide Intermediate 35A (0.78g, 60%). MS (ESI)m/z: 222.9/224.8 (M+H)⁺.

Intermediate 35. Intermediate 35 was prepared following the proceduresdescribed in Intermediate 30, by replacing Intermediate 30A withIntermediate 35A. ¹H NMR (400 MHz, CD₃OD) δ ppm 8.18 (s, 1 H), 4.16 (s,3 H). MS (ESI) m/z: 246.9/248.8 (M+H)⁺.

INTERMEDIATE 364,6-Difluoro-1-fluoromethyl-1H-benzoimidazole-5-carboxylic acid

Intermediate 36A. 4,6-Difluoro-1-(fluoromethyl)-1H-benzo[d]imidazole:(Reference: Tetrahedron, 63:10569-10575 (2007).) To a solution of4,6-difluoro-1H-benzo[d]imidazole (100 mg, 0.649 mmol) in DMF (5 mL) wasadded NaH (57.1 mg, 1.43 mmol) and the resulting solution was stirredfor 0.5h at rt. The solution was cooled down to −78° C. and FCH₂Cl wasbubbled in for 10 min. The reaction mixture was then sealed in themicrowave vial and stirred at 80° C. for 2h. The reaction mixture wasdiluted with EtOAc (30 ml) and washed with 1N HCl (20 mL), then aqNH₄Cl. Organic solution was concentrated and purified on reverse phasechromatography to provide Intermediate 36A (52 mg, 43%). ¹H NMR (500MHz, CDCl₃) δ ppm 8.02 (d, 2 H), 7.29-7.40 (m, 1 H), 7.00-7.13 (m, 1 H),6.82-6.98 (m, 2 H), 6.29 (s, 1 H), 6.18 (d, J=5.5 Hz, 2 H), 6.07 (s, 1H), 1.59 (s, 2 H). MS (ESI) m/z: 187.0 (M+H)⁺.

Intermediate 36. Intermediate 36 was prepared following the proceduredescribed in Intermediate 30, by replacing Intermediate 30B withIntermediate 36A. MS (ESI) m/z: 231.1 (M+H)⁺.

INTERMEDIATE 37 2-Methyl-propane-2-sulfinic acid{(S)-1-[4-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-but-3-enyl}-amide

Intermediate 37A.2,4,5-Tribromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole: To acooled (0° C.) suspension of sodium hydride (0.9 g, 0.03 mole) in THF(50 mL) was added dropwise a solution of 2, 4, 5-tribromo imidazole (5g, 0.016 mol) in THF (50 mL). After 1h, a solution oftrimethylsilylethoxymethyl chloride (SEMCl) (3 mL, 0.017 mol) in THF (30mL) was added dropwise. The reaction mixture was quenched with saturatedammonium chloride solution and then the reaction was extracted withethyl acetate [3×100 mL]. The organic layers were combined and washedwith 10% sodium bicarbonate solution, water, brine, dried over sodiumsulfate, filtered and concentrated to yield 7.2 g of Intermediate 37A aspale, yellow oil which solidified on standing. The material was used inthe next step without further purification. MS (ESI) m/z: 435 (M+2+H)⁺.

Intermediate 37B.4,5-Dibromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde:To a cooled (−78° C.) solution of Intermediate 37A (16 g, 0.03 mol) inTHF (160 mL) was added a solution of n-BuLi (13.5 mL, 3M in hexane; 0.04mol) dropwise. After 1h, DMF (14 mL, 0.2 mol) was added dropwise. After1h, the reaction was quenched with saturated ammonium chloride solutionand then the reaction was allowed to warm to RT. The reaction wasextracted with ethyl acetate [2×100 mL]. The organic layers werecombined and washed with 10% sodium bicarbonate solution, water, brineand then concentrated. Purification by normal phase chromatography(gradient elution pet ether: ethyl acetate) gave 11.5 g (40%) ofIntermediate 37B. MS (ESI) m/z: 384.1 (M)⁺.

Intermediate 37C.(S,E)-N-((4,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methylene)-2-methylpropane-2-sulfinamide:To a solution of Intermediate 37B (35 g, 0.09 mol) in methylene chloride(350 mL) was added (S)-(−)-2-Methyl-2-propanesulfinamide (22 g, 0.18mole) and anhydrous copper sulfate (72 gc 0.45 mol). The resultingsuspension was stirred at RT. After 20 h, the reaction was filteredthrough CELITE®. The filtrate was concentrated and purification bynormal phase chromatography (gradient elution pet ether:ethyl acetate)gave 42 g (94%) of Intermediate 37C as a pale yellow oil whichsolidified on standing. MS (ESI) m/z: 487.3 (M+H)⁺.

Intermediate 37D. 2-Methyl-propane-2-sulfinic acid{(S)-1-[4,5-dibromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-but-3-enyl}-amide:To a cooled (−78° C.) solution of Intermediate 37C (17 g, 0.03 mole) inTHF (170 mL) was added allylmagnesium bromide (1M in diethylether, 52.3mL, 0.05 mol) dropwise. After 1 h, the reaction was quenched withsaturated ammonium chloride solution and then the reaction was allowedto warm to RT. The reaction mixture was extracted with ethyl acetate(2×250 mL). The organic layers were combined and washed with sodiumbicarbonate solution, brine, water, dried over anhydrous sodium sulfate,filtered and concentrated. Purification by normal phase chromatography(gradient elution; hexane:ethyl acetate) gave 25 g (67%) of Intermediate37D, as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 5.71 (m, 1H), 5.60(d, 1H, J=11.6 Hz), 5.28 (m, 1H), 5.06 (m, 2H), 4.57 (q, 1H, J=7.2 Hz),3.98 (d, 1H, J=8.4 Hz), 3.55 (m, 2H), 2.70 (t, 2H, 7.2 Hz), 1.2 (s, 9H),0.92 (m, 2H), −0.01 (s, 9H). MS (ESI) m/z: 529.4 (M+H)⁺.

Intermediate 37. A solution of Intermediate 37D (5.25 g, 9.92 mmol) inTHF (33.1 mL) was degassed with argon for 15 min. The solution wascooled to −3° C. (ice/brine) and isopropylmagnesium chloride, lithiumchloride complex in THF (8.00 mL, 10.4 mmol) was added dropwise over 20min, keeping the temperature below 0° C. during the addition. After 30min, the second equivalent of isopropylmagnesium chloride, lithiumchloride complex in THF (8.00 mL, 10.4 mmol) was added dropwise over 20min, keeping the temperature below 0° C. during the addition. After 30min, the reaction was quenched with sat. ammonium chloride (30 mL) andthe reaction was allowed to warm to RT. The reaction was partitionedbetween EtOAc and sat. ammonium chloride and the layers were separated.The aqueous layer was extracted with EtOAc (1×). The organic layers werecombined and washed with sat. NaHCO₃, brine, dried over sodium sulfate,filtered and concentrated to give clear, yellow viscous oil weighing4.67 g. Purification by normal phase chromatography gave 3.98 g (89%) ofIntermediate 37, as a white solid. ¹H NMR (500 MHz, CD₃OD) δ ppm 7.20(s, 1 H), 5.69-5.82 (m, 1 H), 5.49 (d, J=11.3 Hz, 1 H), 5.30 (d, J=11.3Hz, 1 H), 5.09 (dd, J=17.1, 1.7 Hz, 1 H), 5.04 (d, J=10.5 Hz, 1 H), 4.62(t, J=7.3 Hz, 1 H), 3.51-3.67 (m, 2H), 2.69 (t, J=7.3 Hz, 2 H), 1.20 (s,9 H), 0.85-1.04 (m, 2 H), 0.00 (s, 9 H). MS (ESI) m/z: 450.1 (M+H)⁺.[α]_(D) ^(23.6)=+70.13 (c=1.70; chloroform).

Alternatively, Intermediate 37 can be prepared by the followingsequence:

Intermediate 37E.2,4-Dibromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole: To acooled (0° C.) suspension of NaH (1.062 g, 26.6 mmol) in THF (44.3 mL)was added dropwise over 20 min. a clear, pale yellow solution of2,4-dibromo-1H-imidazole (5.00 g, 22.14 mmol) in THF (20 mL). Theresulting purple-gray suspension was stirred at 0° C. for 1h. Next,SEMCl (4.71 mL, 26.6 mmol) was added dropwise. The reaction wasmaintained at 0° C. for 1h and then it was quenched with the slowaddition of sat. ammonium chloride. The reaction was diluted with EtOAcand the layers were separated. The aqueous layer was extracted withEtOAc (2×). The combined organic layers were washed with sat. NaHCO₃,brine, dried over sulfate, filtered and concentrated to give a clearliquid weighing 9.06 g. Purification by normal phase chromatography gave5.97 g (76%) of Intermediate 37E, as a clear, colorless liquid. Ratio ofregioisomers by HPLC was 14.7:1. MS (ESI) m/z: 357.0 (M+2+H)⁺.

Intermediate 37F.4-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde:To a cooled (−78° C.) clear, colorless solution of Intermediate 37E (1.0g, 2.81 mmol) in THF (9.36 mL) was added dropwise over 10 min. n-BuLi(1.930 mL, 3.09 mmol). The resulting clear, golden yellow solution wasstirred at −78° C. for 1 h and then DMF (1.087 mL, 14.04 mmol) wasadded. The reaction was stirred at −78° C. for 1 h and then the reactionwas quenched with sat. ammonium chloride and the reaction was allowed towarm to RT. The reaction was partitioned between EtOAc and water and thelayers were separated. The organic layer was washed with sat. NaHCO₃,brine, dried over sodium sulfate, filtered, and concentrated.Purification by normal phase chromatography gave 0.130 g (16%) ofIntermediate 37F, as a white solid. MS (ESI) m/z: 339.1 (M+CH₄O+2+H)⁺,consistent with hemiacetal of methanol addition to the aldehyde.

Intermediate 37. Intermediate 37 was prepared by following theprocedures described in Intermediate 37C, by replacing Intermediate 37Bwith Intermediate 37F; followed by procedure described in Intermediate37D which gave a 9:1 mixture of diastereomers.

INTERMEDIATE 38 4,6-Difluoro-1,3-dimethyl-1H-indazole-5-carboxylic acid

Intermediate 38A. 4,6-Difluoro-1,3-dimethyl-1H-indazole: K₂CO₃ (1.191 g,8.61 mmol) and copper(II) oxide (0.023 g, 0.287 mmol) were weighed intoa microwave tube. Vacuum and filled with Ar for several times.Methylhydrazine (0.363 ml, 6.89 mmol) was added. The reaction was cooleddown to 0° C. 1-(2,4,6-trifluorophenyl)ethanone (0.767 ml, 5.74 mmol)was added dropwise. The tube was placed in an oil bath and heated at100° C. for 4 hrs, then cooled down to rt overnight. The reactionmixture was diluted with EtOAc, washed with H₂O, brine, dried overMgSO₄. Purification by normal phase chromatography gave 877 mg (84%) ofIntermediate 38A as a white solid. MS (ESI) m/z: 183.0 (M+H)⁺.

Intermediate 38. In a flame-dried 25 ml RBF, diisopropylamine (0.494 ml,3.52 mmol) in THF (14.68 ml) was cooled down to 0° C. under Ar.Butyllithium (1.6M in Hexane) (1.571 ml, 2.51 mmol) was added. Thereaction was stirred at 0° C. for 1 hr, before cooling down to −78° C.4,6-difluoro-1,3-dimethyl-1H-indazole (535 mg, 2.94 mmol) in 4 ml dryTHF was added dropwise. The reaction was stirred at −78° C. for 1 hrs,before dry ice was added to the reaction. The reaction was stirred at−78° C. for 30 mins and then warmed up to rt and stirred at rtovernight. The reaction was concentrated, diluted with EtOAc, washedwith H₂O. The aqueous layer was acidified with 1N HCl. It was filteredand the white solid was dried in a vacuum oven to give 160 mg (24%) ofIntermediate 38 as a white solid. MS (ESI) m/z: 227.0 (M+H)⁺.

INTERMEDIATE 39 4-Amino-3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-benzoicacid methyl ester

A flame-dried flask, equipped with a reflux condensor, containing methyl4-amino-3-bromobenzoate (2.5 g, 10.87 mmol), bis(neopentylglycolato)diboron (3.07 g, 13.58 mmol), potassium acetate (3.20 g, 32.6mmol), and PdCl₂(dppf)-CH₂Cl₂ adduct (0.222 g, 0.272 mmol) was addeddegassed DMSO (31.0 mL). The resulting dark red-brown suspension waswarmed to 85° C. After 2.5 h, the resulting dark black reaction wascooled to RT and poured into cold water (100 mL) to give a suspension.The suspension was extracted with EtOAc (3×). The combined organiclayers were washed with sat. NaHCO₃, brine, dried over sodium sulfate,filtered and concentrated to give a brown solid weighing 3.1 g.Purification by normal phase chromatography gave 1.64 g (55%) ofIntermediate 39 as a pale, yellow solid. ¹H NMR (500 MHz, CDCl₃) δ ppm8.35 (d, J=2.20 Hz, 1 H), 7.84 (dd, J=8.53, 2.20 Hz, 1 H), 6.52 (d,J=8.53 Hz, 1 H), 5.25 (br. s., 2 H), 3.84 (s, 3 H), 3.79 (s, 4 H), 1.03(s, 6 H). MS (ESI) m/z: 196.0 (M-C₅ H₈+H)⁺.

INTERMEDIATE 40(E)-3-(3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl)acrylic acid

Intermediate 40 was prepared following the procedures described inIntermediate 24, by replacing 5-chloro-2-(difluoromethoxy) benzaldehydewith 3-chloro-2-fluoro-6-(trifluoromethyl)benzaldehyde. MS (ESI) m/z:292 (M+Na)⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.87 (1 H, dd, J=16.17, 2.02Hz), 7.49-7.62 (2 H, m), 6.67 (1 H, dd, J=16.30, 1.39 Hz).

EXAMPLE 1(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-(E)-(S)-8-oxa-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl-acrylamide,1 TFA salt

1A. (S)-2-tert-Butoxycarbonylamino-pent-4-enoic acid2-(2-but-3-enyloxy-phenyl)-2-oxo-ethyl ester: A suspension of(S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (515 mg, 2.394 mmol)and potassium hydrogen carbonate (0.288 g, 2.87 mmol) in DMF (12.00 mL)was stirred at rt for 20 min. The reaction was then cooled to 0° C. andIntermediate 6 (0.773g, 2.87 mmol) was added. The resulting yellowsolution was allowed to warm to rt. After stirring overnight, thereaction was cooled to 0° C. and then poured into cold water to give awhite suspension. The white suspension was then extracted with EtOAc(3×75 mL). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated to give 1.072 g of 1A as ayellow oil. This was used without further purification. MS (ESI) m/z:304.3 (M-C₅H₈O₂+H)⁺.

1B.{(S)-1-[4-(2-But-3-enyloxy-phenyl)-1H-imidazol-2-yl]-but-3-enyl}-carbamicacid tert-butyl ester: Compound 1A (1.07 g, 2.66 mmol) was dissolved inxylene (26.6 mL) and divided evenly between two 20-mL microwave vials.Next ammonium acetate (2.047 g, 26.6 mmol) was added to each vial. Thevials were microwaved at 140° C. for 30 min. The resulting bright orangesolutions were combined, partitioned between EtOAc and sat. NaHCO₃ andthe layers were separated. The aqueous layer was extracted with EtOAc(2×100 mL). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated to give a peach residue.Purification by normal phase chromatography gave 0.626g (62%) of 1B as asticky, yellow solid. MS (ESI) m/z: 384.4 (M+H)⁺.

1C.{(S)-1-[4-(2-But-3-enyloxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-but-3-enyl}-carbamicacid tert-butyl ester: To a cooled (0° C.) suspension of NaH (58.7 mg,1.468 mmol) in DMF (2.06 mL) was added dropwise a solution of 1B (536.2mg, 1.40 mmol) in DMF (1.3 mL). The resulting orange solution wasallowed to warm to rt. After 1 h, the reaction was cooled to 0° C. andSEMCl (0.27 mL, 1.52 mmol) was added dropwise. The resulting peachsolution was allowed to warm to rt. After 1h and 45 min, the cloudyyellow mixture was cooled to 0° C. and quenched with water (20 mL). Thereaction was extracted with EtOAc (3×20 mL). The combined organic layerswere washed with water (3×6 mL), dried over Na₂SO₄, filtered andconcentrated. Purification by normal phase chromatography gave 462.5 mg(64%) of 1C as a pale yellow oil. MS (ESI) m/z: 514.3 (M+H)⁺.

1D.[(E)-(S)-16-(2-Trimethylsilanyl-ethoxymethyl)-8-oxa-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl]-carbamicacid tert-butyl ester, 1 TFA salt; and 1E.[(Z)-(S)-16-(2-Trimethylsilanyl-ethoxymethyl)-8-oxa-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl]-carbamic acid tert-butyl ester, 1 TFAsalt: (Flask 1): To a flame-dried RBF was added Grubbs (II) (681 mg,0.802 mmol). The flask was degassed with argon for several minutes andthen degassed DCM (10 mL) was added to give a clear, burgundy solution.(Flask 2): To a separate flame-dried RBF was added 1C (412 mg, 0.802mmol), pTsOH monohydrate (168 mg, 0.882 mmol) and DCM (779 mL). Theflask was equipped with a reflux condenser and the solution was degassedwith argon for 30 min. Next, the reaction was warmed to 40° C. After 1h,the solution of Grubbs (II) was added dropwise. After 1 h, the reactionwas cooled to rt and washed with NaHCO₃, brine, dried over MgSO₄,filtered and concentrated. Purification by normal phase chromatographygave a pale, brown oil. Further purification by reverse phasechromatography gave 78.6 mg (20%) of 1D (E-alkene) as a pale brown oiland 33.2 mg (9%) of 1E (Z-alkene) as a pale, brown oil. For 1D: MS (ESI)m/z: 486.5 (M+H)⁺. For 1E: MS (ESI) m/z: 486.5 (M+H)⁺.

1F.(E)-(S)-(8-Pxa-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl)amine,2 TFA: A yellow solution of 1D (59.2 mg, 0.122 mmol) in 5M HCl (2.50 mL,82 mmol) and EtOH (2.44 mL) was heated to 50° C. After stirringovernight, the reaction was concentrated to remove EtOH and theremaining aqueous layer was adjusted to pH>10 with sat. K₂CO₃. Thereaction was extracted with EtOAc (3×). The combined organic layers weredried over Na₂SO₄, filtered and concentrated to give a brown residue.Purification by reverse phase chromatography gave 0.0246 g (42%) of 1Fas a clear, colorless oil. MS (ESI) m/z: 256.3 (M+H)⁺.

1G. Example 1: To a solution of Intermediate 1 (33.5 mg, 0.096 mmol) and1F (24.6 mg, 0.096 mmol) in DMF (0.321 mL) was added Hunig's Base (0.084mL, 0.482 mmol). After 45 min, water was added to give a suspension. Thesolid was collected by filtration. Purification by reverse phasechromatography gave after concentration and lyophilization 0.0195 g(33%) of Example 1 as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm2.40-2.71 (m, 3 H), 2.76-2.88 (m, 1 H), 3.68-3.84 (m, 1 H), 4.21-4.42(m, 1 H), 5.13-5.28 (m, 2 H), 5.77-5.91 (m, 1 H), 6.81 (d, J=15.9 Hz, 1H), 7.14-7.23 (m, 2 H), 7.29 (dd, J=8.2, 1.1 Hz, 1 H), 7.47 (td, J=7.7,1.6 Hz, 1 H), 7.55 (s, 1 H), 7.57-7.62 (m, 2 H), 7.69 (dd, J=8.8, 2.2Hz, 1 H), 8.00 (d, J=2.2 Hz, 1 H), 9.54 (s, 1 H). MS (ESI) m/z: 488.3(M+H)⁺. Analytical HPLC: RT=5.35 min.

EXAMPLE 2(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-(S)-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl-acrylamide,1 TFA salt

2A. (S)-2-(2-Bromophenyl)-2-oxoethyl2-(tert-butoxycarbonylamino)pent-4-enoate: To a clear, colorlesssolution of (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (3.33 g,15.47 mmol) in DMF (38.7 mL) was added potassium hydrogen carbonate(1.859 g, 18.57 mmol). The reaction was stirred for 20 min at rt andthen it was cooled to 0° C. Next a solution of2-bromo-1-(2-bromophenyl)ethanone (4.3 g, 15.47 mmol) in DMF (38.7 mL)was added dropwise and the reaction was allowed to warm to rt. After 3h, the reaction was cooled to 0° C., poured into ice-cold water, andthen extracted with EtOAc (3×). The combined organic layers were washedwith water (1×), brine (1×), dried over sodium sulfate, filtered andconcentrated to give 2A (6.37 g) as a yellow oil which solidified onstorage in the freezer. MS (ESI) m/z: 410.2 (M−H)⁻, 412.2 (M+2-H)⁻. Thematerial was used in the next step without further purification.

2B. (S)-tert-Butyl1-(5-(2-bromophenyl)-1H-imidazol-2-yl)but-3-enylcarbamate: To the clear,yellow solution of 2A (6.37 g, 15.45 mmol) in xylene (155 mL) was addedammonium acetate (11.91 g, 155 mmol). The reaction mixture was heated toreflux with a Dean-Stark trap to remove water azeotropically. After 4 h,the reaction was cooled to rt, diluted with EtOAc (500 mL) and thenwashed with sat. sodium bicarbonate, brine, dried over sodium sulfate,filtered, and concentrated to give a brown residue. Purification bynormal phase chromatography afforded 2B (2.768 g, 45.7%) as a yellowsolid. MS (ESI) m/z: 392.3 (M+H)⁺, 394.3 (M+2+H)⁺.

2C. (S)-tert-Butyl1-(4-(2-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-enylcarbamate:To a cooled (0° C.), suspension of NaH (60% dispersion in mineral oil,0.299 g, 7.48 mmol) in THF (10.0 mL) was added dropwise a solution of 2B(2.668 g, 6.80 mmol) in THF (15.0 mL). Gas evolution was observed. Theflask containing 2B was rinsed with THF (2.2 mL) and then this solutionwas added to the reaction mixture. The resulting clear orange solutionwas stirred at 0° C. for 30 min, then SEM-Cl (1.206 mL, 6.80 mmol) wasadded dropwise. The resulting orange solution was maintained at 0° C.After 3 h, the reaction was quenched with sat. ammonium chloride anddiluted with EtOAc (200 mL) and water. The layers were separated and theaqueous layer was extracted with EtOAc (1×). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered, andconcentrated to give clear orange oil. Purification by normal phasechromatography gave 2C (2.76 g, 78%) as a yellow oil. MS (ESI) m/z:522.5 (M+H)⁺, 524.5 (M+2+H)⁺.

2D. (S)-tert-Butyl1-(4-(2-(pent-4-enyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-enylcarbamate:To a flame-dried, thick-walled vial was placed 2C (1.085 g, 2.076 mmol),pent-4-enylboronic acid (0.757 g, 6.64 mmol), silver oxide (1.203 g,5.19 mmol), potassium carbonate (1.722 g, 12.46 mmol), andPdCl₂(dppf)-CH₂Cl₂ adduct (0.170 g, 0.208 mmol). The vial was purgedwith argon for several minutes and then degassed THF (8.3 mL) was added.The vial was sealed with a teflon-coated screw cap and the blacksuspension was warmed to 80° C. After 16 h the reaction was cooled tort. The reaction mixture was diluted with EtOAc, washed with water, sat.sodium bicarbonate, brine, dried over sodium sulfate, filtered andconcentrated to give an orange-brown residue. Purification by normalphase chromatography yielded a clear, colorless oil which was a mixtureof 2D and starting material. The material was purified further byreverse phase chromatography. The pure fractions were neutralized withsat. sodium bicarbonate and then concentrated to remove the organicsolvent. The remaining residue was extracted with EtOAc (2×). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated to afford 2D (0.21 g, 20%) as aclear, colorless oil. MS (ESI) m/z: 512.6 (M+H)⁺.

2E.[(E)-(S)-16-(2-Trimethylsilanyl-ethoxymethyl)-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl]-carbamicacid tert-butyl ester and 2F.[(Z)-(S)-16-(2-Trimethylsilanyl-ethoxymethyl)-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl]-carbamicacid tert-butyl ester: (Flask 1): To a flame-dried flask was addedGrubbs (II) (0.139 g, 0.164 mmol). The flask was degassed with argon forseveral minutes and then degassed DCM (2 mL) was added to give a clear,burgundy solution. (Flask 2): To a separate flame-dried RBF was added 2D(0.21 g, 0.410 mmol), p-toluenesulfonic acid monohydrate (0.086 g, 0.451mmol) and DCM (420 mL). The flask was equipped with a reflux condenserand the solution was degassed with argon for 30 min. The reaction washeated to 40° C. After 1 h, the solution of Grubbs (II) was addeddropwise. After 1 h, the reaction was cooled to rt, washed with sat.sodium bicarbonate, brine, dried over MgSO₄, filtered and concentratedto give a brown foam. Purification by reverse phase chromatography gave,after neutralization and extractive workup as described in 2D, 2E (0.09g, 45.3%, E-alkene) as a yellow solid and 2F (0.035 g, 17.6%, Z-alkene)as a yellow solid. For 2E: MS (ESI) m/z: 484.6 (M+H)⁺. For 2F: MS (ESI)m/z: 484.6 (M+H)⁺.

2G.[(S)-16-(2-Trimethylsilanyl-ethoxymethyl)-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester: To the solution of 2E and 2F (mixture of E/Zisomers) (0.049 g, 0.101 mmol) in MeOH (3 mL) was added 10% palladium oncarbon (10.78 mg, 10.13 μmol). The reaction mixture was stirred underH₂-balloon. After 2 h, the reaction was filtered through a 0.45 μm glassmicrofiber filter (GMF) and the Pd/C was rinsed with MeOH. The filtratewas concentrated to give 2G (0.046 g, 93%) as a clear, colorlessresidue. MS (ESI) m/z: 486.7 (M+H)⁺. The material was used in the nextstep without further purification.

2H. Example 2 was prepared by following the procedures described in step1F, by replacing 1D with 2G; followed by step 1G. ¹ H NMR (500 MHz, 50°C., CD₃OD) δ ppm 9.47 (s, 1 H), 7.96 (d, J=2.2 Hz, 1 H), 7.67 (dd,J=8.8, 2.2 Hz, 1 H), 7.57 (d, J=8.8 Hz, 1 H), 7.43-7.49 (m, 3 H),7.32-7.39 (m, 2 H), 7.18 (d, J=16.0 Hz, 1 H), 6.76 (dd, J=15.7, 3.6 Hz,1 H), 4.99-5.04 (m, 1 H), 2.52-2.60 (m, 1 H), 2.40-2.48 (m, 1 H),2.18-2.26 (m, 1 H), 1.84-1.90 (m, 1 H), 1.31-1.58 (m, 4 H), 1.21-1.29(m, 2 H), 0.87-1.01 (m, 1 H), 0.40-0.54 (m, 1 H). MS (ESI) m/z: 488.0(M+H)⁺. Analytical HPLC: RT=5.78 min.

EXAMPLE 3 2 TFA Salt

3A.(E)-(S)-(16,18-Diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl)amine,2 TFA salt: This compound was prepared following the proceduresdescribed in 1F, by replacing 1D with 2E. MS (ESI) m/z: 254.5 (M+H)⁺.

3B.{4-[(E)-(S)-(16,18-Diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl)carbamoyl]-cyclohexylmethyl}-carbamicacid tert-butyl ester: To a solution of 3A (0.014 g, 0.029 mmol) in DMF(0.5 mL) was added(1r,4r)-4-((tert-butoxycarbonylamino)methyl)cyclohexanecarboxylic acid(8.23 mg, 0.032 mmol), EDC (0.011 g, 0.058 mmol), HOBt (8.91 mg, 0.058mmol) and Hunig's base (0.015 g, 0.116 mmol). The reaction was stirredat rt for 16 h and then quenched with water to give a suspension. Thesolid was collected by filtration and then the solid was rinsed withwater, air-dried, and then dried in a vacuum oven (50° C.) for 2 h toafford 3B (0.010 g, 69.8%) as white solid. MS (ESI) m/z: 293.7 (M+H)⁺.The material was used in the next step without further purification.

3C. Example 3: To a solution of 3B (0.01 g, 0.020 mmol) in DCM (0.3 mL)was added TFA (0.3 mL, 3.89 mmol). The reaction was stirred at rt for 1h, and then concentrated. Purification by reverse phase chromatographyafforded Example 3 (0.0095 g, 73.7%) as a white solid. ¹H NMR (500 MHz,50° C., CD₃OD) δ ppm 7.40-7.45 (m, 2 H), 7.38 (s, 1 H), 7.29-7.37 (m, 2H), 5.48-5.56 (m, 1 H), 5.07-5.15 (m, 1 H), 5.01 (dd, J=10.4, 4.9 Hz, 1H), 2.75-2.84 (m, 3 H), 2.58-2.66 (m, 1 H), 2.43-2.51 (m, 2 H),2.35-2.45 (m, 1 H), 1.82-2.03 (m, 6 H), 1.44-1.69 (m, 4 H), 1.20-1.30(m, 1 H), 1.06-1.18 (m, 2 H). MS (ESI) m/z: 393.6 (M+H)⁺. AnalyticalHPLC: RT=3.70 min.

EXAMPLE 4{(E)-(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 4 was prepared following the procedures described in step 2A, byreplacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate 8;followed by steps 2B-2E; 1F; and 1G. ¹ H NMR (50° C., 500 MHz, CD₃OD) δppm 9.47 (s, 1 H), 7.96 (d, J=1.6 Hz, 1 H), 7.67 (d, J=8.8 Hz, 1 H),7.58 (d, J=8.2 Hz, 1 H), 7.46 (s, 1 H), 7.39 (d, J=8.3 Hz, 1 H),7.29-7.37 (m, 2 H), 7.19 (d, J=15.4 Hz, 1 H), 6.76 (d, J=15.4 Hz, 1 H),5.50-5.60 (m, 1 H), 5.09-5.19 (m, 1 H), 5.02-5.09 (m, 1 H), 3.75 (s, 3H), 2.77-2.86 (m, 1 H), 2.40-2.60 (m, 3 H), 1.95-2.05 (m, 1 H),1.85-1.95 (m, 1 H), 1.49-1.62 (m, 1 H), 1.25-1.38 (m, 1 H). MS (ESI)m/z: 559.1 (M+H)⁺ and 561.1 (M+2+H)⁺. Analytical HPLC (Method D):RT=5.42 min.

EXAMPLE 5(E)-N—((S)-17-Chloro-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylamide,1 TFA salt

5A.[(S)-17-Chloro-16-(2-trimethylsilanyl-ethoxymethyl)-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester: To a solution of 2G (0.068 g, 0.140 mmol) inacetonitrile (0.5 mL)/CHCl₃ (0.5 mL) was added NCS (0.022 g, 0.168mmol). The vial was sealed with a teflon-coated screw cap and thereaction was warmed to 65° C. After 3 h, the reaction was cooled to rt.The reaction was diluted with EtOAc, washed with brine, dried oversodium sulfate, filtered and concentrated. Purification by reverse phasechromatography gave, after neutralization of pure fractions and workupas described in step 2D, 0.020 g (27.5%) of 5A as a white solid. MS(ESI) m/z: 520.7 (M+H)⁺.

5B. Example 5 was prepared by following the procedures described in step1F, by replacing 1D with 5A; followed by step 1G. ¹H NMR (500 MHz, 50°C., CD₃OD) δ ppm 9.46 (s, 1 H), 7.97 (d, J=2.2 Hz, 1 H), 7.65 (dd,J=8.2, 2.2 Hz, 1 H), 7.56 (d, J=8.8 Hz, 1 H), 7.35-7.39 (m, 2 H), 7.32(s, 1 H), 7.26-7.31 (m, 2 H), 7.14 (d, J=15.4 Hz, 1 H), 6.77 (d, J=15.4Hz, 1 H), 4.86 (dd, J=10.4, 5.5 Hz, 1 H), 2.48-2.56 (m, 1 H), 2.36-2.43(m, 1 H), 2.08-2.16 (m, 1 H), 1.60-1.70 (m, 1 H), 1.33-1.55 (m, 3 H),1.11-1.31 (m, 3 H), 0.97-1.08 (m, 1 H), 0.28-0.41 (m, 1 H). MS (ESI)m/z: 522.4 (M+H)⁺. Analytical HPLC: RT=8.48 min.

EXAMPLE 6{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 6 was prepared following the procedures described in step 2A, byreplacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate 8;followed by steps 2B-2G; 1F, by replacing ethanol with methanol and byrunning the reaction at 75° C.; and 1G. ¹H NMR (500 MHz, 50° C., CD₃OD)δ ppm 9.47 (s, 1 H), 7.95 (d, J=2.2 Hz, 1 H), 7.67 (dd, J=8.8, 2.2 Hz, 1H), 7.57 (d, J=8.2 Hz, 1 H), 7.46 (d, J=2.2 Hz, 1H), 7.41-7.44 (m, 2 H),7.37 (d, J=8.3 Hz, 1 H), 7.17 (d, J=15.9 Hz, 1 H), 6.77 (d, J=15.9 Hz, 1H), 5.01 (dd, J=9.1, 5.8 Hz, 1 H), 3.75 (s, 3 H), 2.47-2.56 (m, 1 H),2.36-2.44 (m, 1 H), 2.17-2.25 (m, 1 H), 1.82-1.91 (m, 1 H), 1.31-1.56(m, 4 H), 1.23-1.26 (m, 2 H), 0.87-0.98 (m, 1 H), 0.38-0.53 (m, 1 H). MS(ESI) m/z: 561.1 (M+H)⁺. Analytical HPLC: RT=5.45 min.

EXAMPLE 7{(S)-17-Chloro-14-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

To the solution of Example 6 (0.012 g, 0.018 mmol) in acetonitrile (0.3mL)/chloroform (0.300 mL) was added NCS (2.85 mg, 0.021 mmol). The vialwas sealed with a teflon-coated screw cap and the reaction was warmed to65° C. After 4 h, additional NCS (2.85 mg, 0.021 mmol) was added. Afteranother 1 h, the reaction was cooled to rt, and then concentrated.Purification by reverse phase chromatography afforded 0.0040 g (30.9%)of Example 7 as a yellow solid. ¹H NMR (500 MHz, 50° C., CD₃OD) δ ppm9.46 (s, 1 H), 7.97 (d, J=2.2 Hz, 1 H), 7.65 (dd, J=8.8, 2.2 Hz, 1 H),7.55 (d, J=8.3 Hz, 1 H), 7.40 (d, J=2.2 Hz, 1 H), 7.36 (dd, J=8.3, 1.6Hz, 1 H), 7.27 (d, J=8.2 Hz, 1 H), 7.13 (d, J=15.4 Hz, 1 H), 6.77 (d,J=15.9 Hz, 1 H), 4.85 (dd, J=10.4, 5.5 Hz, 1 H), 3.75 (s, 3 H),2.43-2.52 (m, 1 H), 2.31-2.40 (m, 1 H), 2.05-2.15 (m, 1H), 1.57-1.68 (m,1 H), 1.10-1.53 (m, 6 H), 0.95-1.07 (m, 1 H), 0.26-0.38 (m, 1 H). MS(ESI) m/z: 561.1 (M+H)⁺. Analytical HPLC: RT=7.48 min.

EXAMPLE 8{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acroyolamino]-8-oxa-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 8 was prepared following the procedures described in step 2A, byreplacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate 7;followed by steps 2B-2C; 2E/2F-2G; 1F, by replacing ethanol withmethanol and by running the reaction at 75° C.; and 1G. ¹H NMR (500 MHz,CD₃OD) δ ppm 9.52 (s, 1 H), 7.98 (d, J=2.2 Hz, 1 H), 7.68 (dd, J=8.2,2.2 Hz, 1 H), 7.59 (d, J=8.2 Hz, 1 H), 7.48-7.52 (m, 2 H), 7.46 (d,J=8.2 Hz, 1 H), 7.21 (dd, J=8.8, 2.2 Hz, 1 H), 7.16 (d, J=15.9 Hz, 1H),6.78 (d, J=15.9 Hz, 1 H), 5.14 (dd, J=10.4, 6.0 Hz, 1 H), 3.82-3.88 (m,1 H), 3.75 (s, 3 H), 3.67-3.72 (m, 1 H), 2.19-2.28 (m, 1 H), 1.84-1.99(m, 2 H), 1.46-1.62 (m, 2 H), 1.35-1.45 (m, 1 H), 1.11-1.21 (m, 1 H),0.88-0.99 (m, 1 H). MS (ESI) m/z: 562.9 (M+H)⁺. Analytical HPLC: RT=5.65min.

EXAMPLE 9{(S)-17-Chloro-14-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8-oxa-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamic acid methyl ester, 1 TFA salt

To a solution of Example 8 (0.013 g, 0.019 mmol) in acetonitrile (0.5mL)/chloroform (0.500 mL) was added Hunig's base (6.69 μL, 0.038 mmol).The reaction was stirred at rt for 10 min, then NCS (3.08 mg, 0.023mmol) was added. The vial was sealed with a teflon-coated screw cap andthe reaction was warmed to 65° C. After 4 h, additional NCS (3.08 mg,0.023 mmol) was added. After another 2 h, the reaction was cooled to rtand then concentrated. Purification by reverse phase chromatographyafforded 0.0050 g (35.5%) of Example 9 as a yellow solid. ¹H NMR (500MHz, CD₃OD) δ ppm 9.52 (s, 1 H), 7.98 (d, J=2.2 Hz, 1 H), 7.67 (dd,J=8.5, 2.5 Hz, 1 H), 7.58 (d, J=8.3 Hz, 1 H), 7.47-7.51 (m, 2 H), 7.20(dd, J=8.8, 2.2 Hz, 1 H), 7.15 (d, J=15.4 Hz, 1 H), 6.77 (d, J=15.4 Hz,1 H), 5.05 (dd, J=10.4, 6.0 Hz, 1 H), 3.80-3.85 (m, 1 H), 3.75 (s, 3 H),3.64-3.70 (m, 1 H), 2.13-2.22 (m, 1 H), 1.81-1.92 (m, 2 H), 1.49-1.61(m, 2 H), 1.30-1.41 (m, 1 H), 1.10-1.20 (m, 1 H), 0.89-1.01 (m, 1 H). MS(ESI) m/z: 597.0 (M+H)⁺. Analytical HPLC: RT=8.09 min.

EXAMPLE 10{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

10A.{3-Bromo-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-3H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: This compound was prepared following the proceduresdescribed in step 2A, by replacing 2-bromo-1-(2-bromophenyl)ethanonewith Intermediate 8; followed by step 2B. MS (ESI) m/z: 467.1 (M+2+H)⁺.

10B.{3-Bromo-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: (The following is an alternative procedure toprocedure 2C). To a cooled (0° C.) solution of 10A (15 g, 32.2 mmol) inTHF (77 mL) was added N,N-dicyclohexylmethylamine (7.52 mL, 35.5 mmol)followed by the dropwise addition of SEM-Cl (6.29 mL, 35.5 mmol). Thereaction was stirred at 0° C. for 2h and then it was allowed to warmslowly to rt. After 18 h, the yellow suspension was diluted with EtOAc,washed with sat. sodium bicarbonate, brine, dried over MgSO₄, filteredand concentrated. Purification by normal phase chromatography gave 12.24g (63.8%) of 10B as an off-white solid. MS (ESI) m/z: 595.1 (M+H)⁺ and597.2 (M+2+H)⁺.

10C.{3-Amino-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: A thick-walled vial containing 10B (2 g, 3.36 mmol),copper(I) iodide (0.128 g, 0.672 mmol), L-proline (0.155 g, 1.343 mmol)and potassium carbonate (1.392 g, 10.07 mmol) in DMSO (6.72 mL) wasvacuumed and back-filled with argon three times. Then 28% aq. ammoniumhydroxide (0.607 mL, 4.37 mmol) was added. The vial was sealed with ateflon-coated screw cap and the reaction was warmed to 85° C. After 20h, the reaction was cooled to rt, diluted with EtOAc, washed with water,brine, dried over sodium sulfate, filtered and concentrated.Purification by normal phase chromatography afforded 1.05 g (58.8%) of10C as a yellow solid. MS (ESI) m/z: 532.5 (M+H)⁺.

10C (Alternative route). Compound 10B (1.0 g, 1.679 mmol), copper(I)iodide (0.032 g, 0.168 mmol), L-proline (0.058 g, 0.504 mmol) and sodiumazide (0.131 g, 2.015 mmol) were added to a 35 mL pressure tube. Next,EtOH (2.52 mL), water (0.839 mL), and 1N NaOH (0.504 mL, 0.504 mmol)were added. The reaction vessel was vacuumed and back-filled with argonthree times. The pressure tube was sealed with a teflon screw cap,containing a viton O-ring, and then the reaction was warmed to 95° C.After 20 h, the reaction was cooled to rt, and additional sodium azide(0.131 g, 2.015 mmol), L-proline (0.058 g, 0.504 mmol), copper(I) iodide(0.032 g, 0.168 mmol), NaOH (0.504 mL, 0.504 mmol) and EtOH (2.52 mL)were added. The vessel was sealed and the reaction was warmed to 95° C.After another 24 h, the reaction was cooled to rt, diluted with EtOAc,washed with water, brine, dried over sodium sulfate, filtered andconcentrated. Purification by normal phase chromatography gave 0.475 g(53.2%) of 10C as an orange solid. MS (ESI) m/z: 532.4 (M+H)⁺.

10D.{3-But-3-enoylamino-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: To a cooled (−10° C.) solution of Hunig's base (0.300mL, 1.715 mmol), but-3-enoic acid (0.049 g, 0.572 mmol) and 10C (0.304g, 0.572 mmol) in ethyl acetate (16.34 mL) was added 1-propanephosphonicacid cyclic anhydride (T3P) (50% in EtOAc, 0.674 mL, 1.143 mmol). After5 min, the reaction was allowed to warm to rt. After 1 h at rt, thereaction was concentrated. Purification by normal phase chromatographygave 0.30 g (87%) of 10D as a yellow solid. MS (ESI) m/z: 600.3 (M+H)⁺.

10E.[(E)-(S)-14-tert-Butoxycarbonylamino-9-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-5-yl]-carbamicacid methyl ester; and 10F.[(Z)-(S)-14-tert-Butoxycarbonylamino-9-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-5-yl]-carbamicacid methyl ester: Compound 10E, the E-alkene, and compound 10F, theZ-alkene, were prepared following the procedure described in 2E/2F, byreplacing 2D with 10D. MS (ESI) m/z: 572.2 (M+H)⁺.

10G.[(S)-14-tert-Butoxycarbonylamino-9-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]-carbamicacid methyl ester: To a suspension of 10E (0.25 g, 0.437 mmol) in MeOH(10 mL)/EtOAc (5 mL) was added 10% palladium on carbon (0.047 g, 0.044mmol). Hydrogen was bubbled through the reaction mixture for 5 min andthen the reaction was stirred vigorously under a hydrogen atmosphere(balloon). After 24 h, the reaction was filtered through a 0.45 μm GMF,rinsing with MeOH, DCM and EtOAc. The filtrate was concentrated andpurification by reverse phase chromatography afforded 0.220 g (88%) of10G, as an off-white solid. MS (ESI) m/z: 574.4 (M+H)⁺.

10H.((S)-14-Amino-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl)-carbamicacid methyl ester, 2 HCl salt: A mixture of 10G (0.099 g, 0.173 mmol)and 4M HCl in dioxane (2 mL, 8.00 mmol) in a sealed tube was heated at50° C. After 2 h, the yellow suspension was cooled to rt and thenconcentrated. The residue was suspended in MeOH (0.2 mL) and Et₂O. Thesolid was collected by filtration. The solid was rinsed with Et₂O,air-dried (very hygroscopic) to afford 0.053 g (73.8%) of 10H as ayellow solid. MS (ESI) m/z: 344.2 (M+H)⁺.

10I. Example 10 was prepared following the procedure described in 1G, byreplacing 1F with 10H. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.51 (s, 1 H), 7.97(d, J=2.2 Hz, 1 H), 7.67 (dd, J=8.2, 2.2 Hz, 1 H), 7.55-7.60 (m, 2 H),7.50 (d, J=8.2 Hz, 1 H), 7.44 (s, 1 H), 7.42 (dd, J=8.3, 2.2 Hz, 1 H),7.13 (d, J=15.4 Hz, 1 H), 6.76 (d, J=15.9 Hz, 1 H), 5.13 (dd, J=10.2,6.3 Hz, 1 H), 3.75 (s, 3 H), 2.42-2.52 (m, 1 H), 2.17-2.29 (m, 1 H),2.05-2.15 (m, 1 H), 1.96 (m, 1 H), 1.51-1.71 (m, 2 H), 1.36-1.49 (m, 1H), 0.92-1.07 (m, 1 H). MS (ESI) m/z: 576.3 (M+H)⁺. Analytical HPLC:RT=4.60 min.

EXAMPLE 11{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acrylamino]-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

Example 11 was prepared following the procedures described in step 10C,by replacing ammonium hydroxide with but-3-enylamine and running thereaction at 90° C.; followed by steps 10E/F; 10G, by replacing themethanol/EtOAc mixture with EtOAc; 1F, by replacing ethanol withmethanol and running the reaction at 75° C.; and 1G. ¹H NMR (400 MHz,CD₃OD) δ ppm 9.54 (s, 1 H), 8.01 (d, J=2.2 Hz, 1 H), 7.82 (s, 1 H), 7.69(dd, J=8.8, 2.2 Hz, 1 H), 7.61 (d, J=8.8 Hz, 1 H), 7.55 (d, J=8.2 Hz, 1H), 7.40 (s, 1 H), 7.28 (dd, J=8.8, 2.2 Hz, 1 H), 7.24 (d, J=15.9 Hz, 1H), 6.81 (d, J=15.4 Hz, 1 H), 5.29 (dd, J=10.7, 6.3 Hz, 1 H), 3.72 (s, 3H), 3.16-3.24 (m, 1 H), 2.93 (t, J=11.5 Hz, 1 H), 2.00-2.20 (m, 3 H),1.82-1.92 (m, 1 H), 1.62-1.76 (m, 2 H), 1.27-1.41 (m, 1 H), 0.78-0.87(m, 1 H). MS (ESI) m/z: 562.2 (M+H)⁺. Analytical HPLC: RT=5.59 min.

EXAMPLE 12{(E)-(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 12 was prepared following the procedures described in step 10H,by replacing 10G with 10E; followed by step 1G. ¹H NMR (500 MHz, CD₃OD)δ ppm 9.52 (s, 1 H), 7.98 (d, J=2.2 Hz, 1 H), 7.66-7.72 (m, 2 H), 7.59(d, J=8.2 Hz, 1 H), 7.45 (s, 2 H), 7.35 (s, 1 H), 7.16 (d, J=15.4 Hz, 1H), 6.76 (d, J=15.4 Hz, 1 H), 5.73-5.82 (m, 1 H), 5.21-5.29 (m, 1 H),5.10 (dd, J=9.1, 5.2 Hz, 1 H), 3.75 (s, 3 H), 2.91-3.03 (m, 2 H),2.81-2.89 (m, 1 H), 2.48-2.59 (m, 1 H). MS (ESI) m/z: 574.1 (M+H)⁺.Analytical HPLC: RT=4.78 min.

EXAMPLE 13{(S)-14-[(E)-3-(3-Chloro-2-fluoro-6-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 13 was prepared following the procedure described in 1G, byreplacing 1F with 10H and by replacing Intermediate 1 with Intermediate3. ¹ H NMR (500 MHz, CD₃OD) δ ppm 9.52 (s, 1 H), 7.78 (t, J=8.2 Hz, 1H), 7.56 (s, 1 H), 7.40-7.52 (m, 4 H), 7.00 (d, J=15.9 Hz, 1 H), 6.81(d, J=15.9 Hz, 1 H), 5.12 (dd, J=9.9, 6.6 Hz, 1 H), 3.75 (s, 3 H),2.42-2.51 (m, 1 H), 2.16-2.26 (m, 1 H), 2.04-2.13 (m, 1 H), 1.89-2.00(m, 1 H), 1.51-1.69 (m, 2 H), 1.36-1.48 (m, 1 H), 0.90-1.03 (m, 1 H). MS(ESI) m/z: 594.3 (M+H)⁺. Analytical HPLC: RT=4.79 min.

EXAMPLE 14{(S)-14-[(E)-3-(2-Acetyl-5-chloro-phenyl)-acryloylamino]-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 14 was prepared following the procedure described in step 1G, byreplacing 1F with 10H, by replacing Intermediate 1 with Intermediate 4,and by using EDC, HOBt, and triethylamine. ¹H NMR (400 MHz, CD₃OD) δ ppm7.97 (d, J=15.4 Hz, 1 H), 7.91 (d, J=8.2 Hz, 1 H), 7.65 (d, J=1.6 Hz, 1H), 7.58 (d, J=2.2 Hz, 1 H), 7.50-7.55 (m, 2 H), 7.47 (s, 1 H), 7.43(dd, J=8.8, 2.2 Hz, 1 H), 6.54 (d, J=15.9 Hz, 1 H), 5.17 (dd, J=10.2,6.3 Hz, 1 H), 3.76 (s, 3 H), 2.59 (s, 3 H), 2.45-2.53 (m, 1 H),2.20-2.31 (m, 1 H), 2.05-2.15 (m, 1 H), 1.92-2.02 (m, 1 H), 1.55-1.72(m, 2 H), 1.40-1.52 (m, 1 H), 0.94-1.07 (m, 1 H). MS (ESI) m/z: 550.2(M+H)⁺. Analytical HPLC: RT=5.01 min.

EXAMPLE 15(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((S)-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl)-acrylamide,1 TFA salt

15A.{(S)-1-[4-(2-Nitro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-but-3-enyl}-carbamicacid tert-butyl ester: This compound was prepared following theprocedures described in step 2A, by replacing2-bromo-1-(2-bromophenyl)ethanone with2-bromo-1-(2-nitrophenyl)ethanone; followed by steps 2B, by replacingxylene with toluene; and 2C. MS (ESI) m/z: 489.4(M+H)⁺.

15B.{(S)-1-[4-(2-Amino-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-but-3-enyl}-carbamicacid tert-butyl ester: To a yellow solution of 15A (1.0441 g, 2.137mmol) in MeOH (14.15 mL) was added zinc dust (1.397 g, 21.37 mmol) andammonium chloride (1.143 g, 21.37 mmol). The gray suspension was stirredvigorously at rt. After 1h, the flask was equipped with a refluxcondenser and the reaction was warmed to 60° C. After 1h, the reactionwas cooled to rt and allowed to stir overnight. The reaction wasfiltered through a 0.45 μm GMF, eluting with methanol. The filtrate wasconcentrated to give a yellow solid. The solid was partitioned betweenEtOAc and 0.5M HCl (aq). The layers were separated and the aqueous layerwas extracted with EtOAc (1×). The combined organic layers were washedwith sat. NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated togive an orange oil. Purification by normal phase chromatography gave0.818g (83%) of 15B as a yellow foam. MS (ESI) m/z: 459.4(M+H)⁺.

15C.(S)-14-Amino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-9-one,2HCl: This compound was prepared following the procedures in step 10D,by replacing 10C with 15B; followed by steps 2E/2F; 2G, by replacing thehydrogen balloon with hydrogen (50-55 psi); and 10H. MS (ESI) m/z:489.4(M+H)⁺.

15D. Example 15: A suspension of Intermediate 2 (0.074g, 0.296 mmol),15C (0.113g, 0.329 mmol), EDC (0.095g, 0.494 mmol), and HOBT (0.076g,0.494 mmol) in DMF (1.65 mL) and Hunig's Base (0.172 mL, 0.988 mmol) wasstirred at rt overnight. Water was added to the brown solution to give asuspension. The mixture was extracted with EtOAc (2×). The organiclayers were combined and washed with sat. NaHCO₃, brine, dried overNa₂SO₄, filtered and concentrated. Purification by reverse phasechromatography gave 0.0964g (47%) of Example 15 as a white solid. ¹H NMR(500 MHz, CD₃OD) δ ppm 0.96-1.13 (m, 1 H), 1.37-1.50 (m, 1 H), 1.51-1.72(m, 2 H), 1.90-2.01 (m, 1 H), 2.05-2.15 (m, 1 H), 2.18-2.28 (m, 1 H),2.44-2.50 (m, 1 H), 5.13 (dd, J=10.2, 6.3 Hz, 1 H), 6.75 (d, J=15.7 Hz,1 H), 7.14 (d, J=15.7 Hz, 1 H), 7.31 (dd, J=7.8, 0.7 Hz, 1 H), 7.44 (td,J=7.6, 1.1 Hz, 1 H), 7.49 (s, 1 H), 7.53 (td, J=7.7, 1.4 Hz, 1 H), 7.58(d, J=8.5 Hz, 1 H), 7.61 (dd, J=7.7, 1.4 Hz, 1 H), 7.67 (dd, J=8.5, 2.5Hz, 1H), 7.97 (d, J=2.2 Hz, 1 H), 9.50 (s, 1 H). MS (ESI) m/z:503.3(M+H)⁺. Analytical HPLC: RT=4.72 min.

EXAMPLE 16 4-Aminomethyl-cyclohexanecarboxylic acid((S)-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl)-amide,2 TFA salt

16A.[4-((S)-9-Oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-ylcarbamoyl)-cyclohexylmethyl]-carbamic acidtert-butyl ester: This compound was prepared following the proceduredescribed in 3B, by replacing 3A with 15C. MS (ESI) m/z: 510.4(M+H)⁺.

16B. Example 16 was prepared following the procedure described in 3C, byreplacing 3B with 16A. ¹H NMR (500 MHz, CD₃OD) δ ppm 0.91-1.18 (m, 3 H),1.28-1.75 (m, 6 H), 1.84-1.98 (m, 5 H), 2.07-2.23 (m, 2 H), 2.33 (tt,J=12.1, 3.3 Hz, 1 H), 2.43-2.53 (m, 1 H), 2.79 (d, J=6.9 Hz, 2 H), 5.05(dd, J=10.7, 6.3 Hz, 1 H), 7.32 (dd, J=7.8, 1.0 Hz, 1 H), 7.44 (td,J=7.7, 1.3 Hz, 1 H), 7.49 (s, 1 H), 7.53 (td, J=7.7, 1.5 Hz, 1 H), 7.60(dd, J=7.7, 1.4 Hz, 1 H). MS (ESI) m/z: 410.4(M+H)⁺. Analytical HPLC:RT=1.56, 2.10 min.

EXAMPLE 17 4-Aminomethyl-cyclohexanecarboxylic acid((S)-17-chloro-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl)-amide,2 TFA salt

17A.[4-((S)-17-Chloro-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-ylcarbamoyl)-cyclohexylmethyl]-carbamic acidtert-butyl ester: Compound 16A was dissolved in EtOAc and washed withsat. NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated to givethe free base of 16A. To a suspension of the free base of 16A (0.067g,0.131 mmol) in acetonitrile (1.32 mL) and chloroform (1.32 mL) was addedNCS (0.018 mg, 0.131 mmol). The thick-walled vial was sealed with ateflon coated screw cap and the reaction was heated to 65° C. After 1hand 35 min, the reaction was cooled to rt and partitioned between EtOAcand water. The layers were separated and the aqueous layer was extractedwith EtOAc (1×). The organic layers were combined, washed with sat.NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated.Purification by reverse phase chromatography gave 0.018 g (17%) of 17Aas a white solid. MS (ESI) m/z: 544.3(M+H)⁺.

17B. Example 17 was prepared following the procedure described in 3C, byreplacing 3B with 17A. ¹H NMR (500 MHz, CD₃OD) δ ppm 0.93-1.17 (m, 3 H),1.34-1.80 (m, 7 H), 1.86-2.10 (m, 6 H), 2.25-2.34 (m, 1 H), 2.36-2.43(m, 1 H), 2.80 (d, J=7.2 Hz, 2 H), 4.93 (dd, J=10.7, 6.1 Hz, 1 H), 7.27(dd, J=7.7, 1.4 Hz, 1H), 7.41 (td, J=7.6, 1.3 Hz, 1 H), 7.46 (td, J=7.6,1.6 Hz, 1 H), 7.60 (dd, J=7.4, 1.4 Hz, 1 H). MS (ESI) m/z: 444.2(M+H)⁺.Analytical HPLC: RT=3.36 min.

EXAMPLE 18{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9,9-dioxo-9λ⁶-thia-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

18A.[4-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-(prop-2-ene-1-sulfonylamino)-phenyl]-carbamicacid methyl ester: To a solution of 10C (178 mg, 0.335 mmol) in CH₂Cl₂(2 mL) was added DIEA (0.117 mL, 0.670 mmol). The reaction was cooled to0° C. Next, a solution of prop-2-ene-1-sulfonyl chloride (54.5 mg, 0.368mmol) in DCM (1 ml) was added dropwise. The resulting mixture wasstirred at 0° C. for 2 h. The reaction was concentrated and purificationby normal phase chromatography gave 18A as a pale yellow solid (124 mg,58%). MS (ESI) m/z: 636.4 (M+H)⁺.

18B. Example 18 was prepared following the procedures described in step2E/2F, by replacing 2D with 18A; followed by steps 2G; 10H; and 1G. ¹HNMR (400 MHz, CD₃OD) δ ppm 9.52 (s, 1 H), 7.98 (d, J=2.2 Hz, 1 H),7.64-7.75 (m, 2 H), 7.54-7.64 (m, 2 H), 7.43-7.54 (m, 2 H), 7.16 (d,J=15.4 Hz, 1 H), 6.78 (d, J=15.4 Hz, 1 H), 5.04 (dd, J=9.3, 4.9 Hz, 1H), 3.75 (s, 3 H), 2.92-3.01 (m, 2 H), 2.16-2.27 (m, 1 H), 1.88-1.98 (m,1 H), 1.69-1.81 (m, 1 H), 1.52-1.66 (m, 1 H), 1.08-1.25 (m, 1 H),0.72-0.93 (m, 1 H). MS (ESI) m/z: 612.3 (M+H)⁺. Analytical HPLC: RT=3.92min (Method B).

EXAMPLE 19{(E)-(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9,9-dioxo-9λ⁶-thia-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 19 was prepared following the procedures described in step 2E,by replacing 2D with 18A; followed by steps 10H; and 1G. ¹H NMR (400MHz, CD₃OD) δ ppm 9.50 (s, 1 H), 7.98 (d, J=2.3 Hz, 1 H), 7.74 (s, 1 H),7.68 (dd, J=8.6, 2.3 Hz, 1 H), 7.54-7.62 (m, 1 H), 7.46-7.54 (m, 2 H),7.43 (s, 1 H), 7.17 (d, J=15.7 Hz, 1 H), 6.78 (d, J=15.7 Hz, 1 H),5.88-6.06 (m, 1 H), 5.07-5.22 (m, 2 H), 3.85-4.08 (m, 2 H), 3.76 (s, 3H), 2.81-2.95 (m, 1 H), 2.47-2.64 (m, 1 H). MS (ESI) m/z: 610.3 (M+H)⁺.Analytical HPLC: RT=3.49 min (Method B).

EXAMPLE 20{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,12,16,18-tetraaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

20A.{(S)-2-Benzyloxycarbonylamino-2-[4-(2-bromo-4-methoxycarbonylamino-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-ethyl}-carbamicacid tert-butyl ester: This compound was prepared following theprocedures described in step 2A, by replacing(S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with(S)-2-benzyloxycarbonylamino-3-tert-butoxycarbonylamino-propionic acidand by replacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate 8;followed by steps 2B; and 10B. MS (ESI) m/z: 720.5(M+H)⁺.

20B.{4-[2-((S)-2-Amino-1-benzyloxycarbonylamino-ethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-bromo-phenyl}-carbamicacid methyl ester: This compound was prepared following the proceduredescribed in 3C, by replacing 3B with 20A. MS (ESI) m/z: 620.3(M+H)⁺.

20C.3-{(S)-2-Benzyloxycarbonylamino-2-[4-(2-bromo-4-methoxycarbonylamino-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-ethylamino}-propionicacid methyl ester: To a mixture of 20B (204 mg, 0.330 mmol), methylacrylate (0.089 mL, 0.989 mmol) and triethylamine (0.230 mL, 1.649 mmol)was added isopropyl alcohol (3 mL) in a sealed microwave tube. Thereaction was stirred at 80° C. overnight. The reaction mixture wasconcentrated to give 20C (208 mg, 90% yield) as a beige solid. MS (ESI)m/z: 706.4(M+H)⁺.

20D.3-({(S)-2-Benzyloxycarbonylamino-2-[4-(2-bromo-4-methoxycarbonylamino-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-ethyl}-tert-butoxycarbonyl-amino)-propionicacid methyl ester: To a solution of 20C (208 mg, 0.295 mmol) in CH₂Cl₂(2952 μL) at 0° C. was added di-tert-butyl dicarbonate (64.4 mg, 0.295mmol) and DMAP (3.61 mg, 0.030 mmol). The reaction mixture was stirredat 0° C. and allowed to warm slowly to rt. After 4 h, the reactionmixture was concentrated and purified by normal phase chromatography togive 20D (180 mg, 0.224 mmol, 76% yield) as a pale yellow solid. MS(ESI) m/z: 806.2(M+H)⁺.

20E.3-({(S)-2-[4-(2-Amino-4-methoxycarbonylamino-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-2-benzyloxycarbonylamino-ethyl}-tert-butoxycarbonyl-amino)-propionicacid: This compound was prepared following the procedure described in10C (alternative route), by replacing 10B with 20D. MS (ESI) m/z:727.6(M+H)⁺.

20F.(S)-14-Benzyloxycarbonylamino-5-methoxycarbonylamino-9-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-8,12,16,18-tetraaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-12-carboxylicacid tert-butyl ester: To a solution of BOP (50.2 mg, 0.113 mmol) in DCM(44.900 ml) and DMF (0.449 ml) at rt was added a solution of 20E (33 mg,0.045 mmol) and DIEA (0.079 ml, 0.454 mmol) in DMF (3 mL) via a syringepump over 5 h. The reaction mixture was concentrated to remove DCM, thendiluted with ethyl acetate and washed with saturated aqueous sodiumbicarbonate. The aqueous layer was extracted with ethyl acetate, and thecombined organic layers were washed with water, brine, dried overmagnesium sulfate, filtered, and concentrated. Normal phasechromatography gave 20F (28 mg, 87% yield) as an off-white solid. MS(ESI) m/z: 709.3(M+H)⁺.

20G. Example 20 was prepared following the procedures described in step2G, by replacing 2E/2F with 20F; followed by steps 1G; and 3C. ¹H NMR(400 MHz, MeOD-d₄) δ ppm 9.49 (s, 1 H) 7.93 (d, J=2.2 Hz, 1 H) 7.66 (dd,J=8.79, 2.2 Hz, 1 H) 7.57 (d, J=8.24 Hz, 2 H) 7.42 (m, 3 H) 7.22 (d,J=15.94 Hz, 1 H) 6.62 (d, J=15.39 Hz, 1 H) 5.40 (dd, J=6.05, 2.75 Hz, 1H) 3.74 (s, 3 H) 3.51-3.69 (m, 2 H) 3.25-3.39 (m, 2 H) 2.89-2.98 (m, 2H). MS (ESI) m/z: 577.3(M+H)⁺. Analytical HPLC: RT=4.72 min.

EXAMPLE 21{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-10,10-difluoro-11-oxo-8,12,16,18-tetraaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 21 was prepared following the procedures described in step 10C(alternative route), by replacing sodium azide with3-amino-2,2-difluoropropanoic acid and by replacing 10B with 20A;followed by steps 3C; 20F; 2G; 1G; and 3C. MS (ESI) m/z: 613.3(M+H)⁺.Analytical HPLC: RT=5.24 min.

EXAMPLE 22{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-10-oxa-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

22A. (S)-2-(2-Bromo-4-nitrophenyl)-2-oxoethyl5-(benzyloxy)-2-(tert-butoxycarbonylamino)pentanoate: This compound wasprepared following the procedure described in 2A, by replacing(S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with(S)-5-(benzyloxy)-2-(tert-butoxycarbonylamino)pentenoic acid andreplacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate 10. MS(ESI) m/z: 565.4 (M+2-H)⁻.

22B. (S)-2-(4-Amino-2-bromophenyl)-2-oxoethyl5-(benzyloxy)-2-(tert-butoxycarbonylamino)pentanoate: To a solution of22A (2.6 g, 4.60 mmol) in ethanol (30 mL) was added iron powder (2.57 g,46.0 mmol). The suspension was mixed briefly and then 1.0 M aqueoushydrochloric acid (2.299 mL, 2.299 mmol) was added. The reaction mixturewas heated to 50° C. After 2 h, the reaction was cooled to rt, dilutedwith ethyl acetate, and filtered through a pad of CELITE®, eluting withethyl acetate. The filtrate was concentrated, re-dissolved in ethylacetate, washed with sat. NaHCO₃, brine, dried over sodium sulfate andconcentrated to give 22B (1.954 g, 79% yield) as a yellow solid. Thematerial was used in the next step without further purification. MS(ESI) m/z: 537.4 (M+2+H)⁺.

22C.{3-Amino-4-[2-((S)-4-benzyloxy-1-tert-butoxycarbonylamino-butyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: This compound was prepared following the proceduresdescribed in step Intermediate 7B, by replacing Intermediate 7A with22B; followed by steps 1B; 10B; and 10C (alternate). MS (ESI) m/z: 640.5(M+H)⁺.

22D.{3-Amino-4-[2-((S)-1-tert-butoxycarbonylamino-4-hydroxy-butyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: To a solution of 22C (0.446 g, 0.697 mmol) in EtOAc(10 mL) was added TFA (0.081 mL, 1.046 mmol). The reaction was stirredat rt for 5 min, then 10% palladium on carbon (0.074 g, 0.070 mmol) wasadded. Hydrogen was bubbled through the reaction for a few minutes, thenthe reaction was stirred vigorously under a hydrogen atmosphere(balloon). After 17 h, the reaction was filtered through a 0.45 micronGMF, rinsing with EtOAc and MeOH. The filtrate was concentrated,redissolved in EtOAc, washed with sat. sodium bicarbonate, brine, driedover sodium sulfate, filtered and concentrated to afford 22D (0.35 g,91%) as a yellow solid. MS (ESI) m/z: 550.4 (M+H)⁺. The material wasused in the next step without further purification.

22E.[(S)-5-Methoxycarbonylamino-9-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-10-oxa-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamic acid tert-butyl ester: To asolution of 22D (0.19 g, 0.346 mmol) in DCM (15.03 mL) at 0° C. wasadded TEA (0.096 mL, 0.691 mmol) followed by 4-nitrophenylcarbonochloridate (0.077 g, 0.380 mmol). After 1 h, the reaction waswarmed to rt. After 18 h, the reaction was concentrated. Purification byreverse phase chromatography afforded 22E (0.049 g, 24.63%), as a yellowsolid. MS (ESI) m/z: 576.5 (M+H)⁺.

22F. Example 22 was prepared following the procedures described in step1F, by replacing 1E with 22E, by replacing ethanol with methanol, and byrunning the reaction at 75° C.; followed by step 1G. ¹H NMR (400 MHz,CD₃OD) δ ppm 9.42 (s, 1 H), 7.76 (d, J=2.2 Hz, 1 H), 7.59-7.68 (m, 2 H),7.46-7.55 (m, 2 H), 7.22 (d, J=8.3 Hz, 1 H), 7.16 (dd, J=8.8, 2.2 Hz, 1H), 6.88 (d, J=15.4 Hz, 1 H), 6.65 (d, J=15.4 Hz, 1 H), 5.26 (t, J=7.7Hz, 1 H), 3.71 (s, 3 H), 3.61 (t, J=6.0 Hz, 2 H), 2.08-2.22 (m, 2 H),1.54-1.74 (m, 2 H). MS (ESI) m/z: 578.3 (M+H)⁺. Analytical HPLC: RT=4.70min.

EXAMPLE 23{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-11-methyl-12-oxo-11,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

23A.(S)-3-[4-(2-Bromo-4-methoxycarbonylamino-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-3-tert-butoxycarbonylamino-propionicacid benzyl ester: This compound was prepared following the proceduresdescribed in 2A, by replacing(S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with(S)-2-tert-butoxycarbonylamino-succinic acid 4-benzyl ester, byreplacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate 8 and byreplacing potassium hydrogen carbonate with potassium carbonate;followed by steps 2B, by replacing xylene with toluene; and 10B. MS(ESI) m/z: 703.3, 705.3 (M+H)⁺.

23B. Methyl-prop-2-ynyl-carbamic acid benzyl ester: To a solution ofN-methylprop-2-yn-1-amine (3.50 g, 50.6 mmol) in DCM (50 mL) were addedTEA (8.47 mL, 60.8 mmol) and Cbz-Cl (7.95 mL, 55.7 mmol) dropwise at 0°C. The reaction was stirred under argon at 0° C. for 1 h. The reactionmixture was diluted with CH₂Cl₂, washed with 1M HCl, saturated NaHCO₃and brine. The organic phase was dried over MgSO₄, filtered andconcentrated to give 23B (10.02 g, 97% yield) as a clear oil. MS (ESI)m/z: 204.1 (M+H)⁺.

23C.(S)-3-[4-{2-[3-(Benzyloxycarbonyl-methyl-amino)-prop-1-ynyl]-4-methoxycarbonylamino-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-3-tert-butoxycarbonylamino-propionicacid benzyl ester: To a solution of 23A (200 mg, 0.284 mmol) in DMF (5mL) was added 23B (69.3 mg, 0.341 mmol), CuI (10.83 mg, 0.057 mmol), TEA(0.119 mL, 0.853 mmol) and Pd(Ph₃P)₄ (32.8 mg, 0.028 mmol). The reactionwas purged with argon for 3 min and then stirred under argon at 90° C.for 6 h. The reaction was cooled to rt and diluted with EtOAc. Theorganic layer was washed with saturated NaHCO₃ and brine, dried overMgSO₄, filtered and concentrated. The crude product was purified bynormal phase chromatography to give 23C (205 mg, 87% yield) as a solid.LC-MS (ESI) m/z: 826.5 (M+H)⁺.

23D.(S)-3-(tert-Butoxycarbonylamino)-3-(4-(4-(methoxycarbonylamino)-2-(3-(methylamino)propyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)propanoicacid, TFA salt: This compound was prepared following the proceduredescribed in 2G, by replacing 2E with 23C. MS (ESI) m/z: 606.4 (M+H)⁺.

23E.[(S)-5-Methoxycarbonylamino-11-methyl-12-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-11,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester: To a solution of DMAP (23.19 mg, 0.190 mmol),DIEA (0.166 mL, 0.949 mmol) and BOP (168 mg, 0.380 mmol) in DCM (20 mL)was added a solution of 23D (115 mg, 0.190 mmol) in DMF (2 mL) at rtthrough a syringe pump over 1.5 h. Upon addition, the reaction wasstirred for another 30 min and the solvent was removed. The crudeproduct was purified by reverse phase chromatography to give 23E (44 mg,39.4% yield) as a solid. MS (ESI) m/z: 588.4 (M+H)⁺.

23F. Example 23 was prepared following the procedures described in step1F, by replacing 1D with 23E and by replacing ethanol with methanol;followed by step 1G. ¹H NMR (400 MHz, CD₃OD, rotamers) δ ppm 9.52 (twosinglets, 1H), 9.36 (s, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.68 (ddd, J=8.6,6.3, 2.3 Hz, 1H), 7.59 (dd, J=8.5, 5.5 Hz, 1H), 7.49-7.43 (m, 1H),7.41-7.33 (m, 3H), 7.19 (two doublets, J=16.0 Hz, 1H), 6.81 (twodoublets, J=15.6 Hz, 1H), 5.49 (dd, J=8.7, 4.8 Hz, 1H), 4.12 (ddd,J=7.3, 6.0, 3.7 Hz, 1H), 3.75 (two singlets, 3H), 3.55-3.43 (m, J=9.2,7.6, 5.9 Hz, 1H), 3.00 (two singlets, 3H), 2.81 (dd, J=13.9, 4.8 Hz,1H), 2.69-2.57 (m, 2H), 2.48-2.28 (m, 1H), 1.91-1.76 (m, 1H), 1.64-1.44(m, 1H). LC-MS (ESI) m/z: 590.2 (M+H)⁺. Analytical HPLC: RT=5.328 min.

EXAMPLE 24(E)-N-((S)-18-Chloro-17,19-diaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-15-yl)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylamide,1 TFA salt

Example 24 was prepared following the procedures described in step 2D,by replacing pent-4-enylboronic acid with hex-5-enylboronic acid;followed by steps 2E/2F; 2G; 1F; 1G; and 7. ¹H NMR (500 MHz, CD₃OD) δppm 9.45 (s, 1 H), 7.95 (d, J=2.2 Hz, 1 H), 7.64 (dd, J=8.2, 2.2 Hz, 1H), 7.55 (d, J=8.3 Hz, 1 H), 7.24-7.35 (m, 4 H), 7.13 (d, J=15.4 Hz, 1H), 6.76 (d, J=15.9 Hz, 1 H), 4.91 (dd, J=9.6, 4.1 Hz, 1 H), 2.68-2.76(m, 1 H), 2.39-2.48 (m, 1 H), 2.06-2.14 (m, 1 H), 1.89-1.99 (m, 1 H),1.56-1.65 (m, 1 H), 1.23-1.45 (m, 7 H), 0.76-0.86 (m, 1 H), 0.49-0.59(m, 1 H). MS (ESI) m/z: 536.4 (M+H)⁺. Analytical HPLC: RT=8.84 min.

EXAMPLE 25{(E)-(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-17,19-diaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 25 was prepared following the procedures described in step 2D,by replacing 2C with 10B and by replacing pent-4-enylboronic acid withhex-5-enylboronic acid; followed by steps 2E; 1F, by replacing ethanolwith methanol and by running the reaction at 50-75° C.; and 1G. ¹H NMR(500 MHz, 50° C., CD₃OD) δ ppm 9.46 (s, 1 H), 7.96 (d, J=2.7 Hz, 1 H),7.64-7.70 (m, 1 H), 7.58 (d, J=8.2 Hz, 1 H), 7.37-7.46 (m, 2 H),7.32-7.35 (m, 1 H), 7.28 (d, J=8.2 Hz, 1 H), 7.19 (d, J=15.9 Hz, 1 H),6.74 (d, J=15.9 Hz, 1 H), 5.48-5.58 (m, 1 H), 5.22-5.31 (m, 1 H), 5.09(dd, J=9.9, 4.4 Hz, 1 H), 3.75 (s, 3 H), 2.81-2.89 (m, 1 H), 2.69-2.78(m, 1 H), 2.52-2.62 (m, 1H), 2.38-2.48 (m, 1 H), 2.06-2.23 (m, 2 H),1.38-1.59 (m, 2 H), 1.09-1.19 (m, 2 H). MS (ESI) m/z: 573.4 (M+H)⁺.Analytical HPLC: RT=5.63 min.

EXAMPLE 26{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acroyoylamino]-17,19-diaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 26 was prepared following the procedures described in step 2D,by replacing 2C with 10B and by replacing pent-4-enylboronic acid withhex-5-enylboronic acid; followed by steps 2E/2F; 2G; 1F, by replacingethanol with methanol and running the reaction at 50-75° C.; and 1G. ¹HNMR (500 MHz, CD₃OD) δ ppm 9.51 (s, 1 H), 7.97 (d, J=2.2 Hz, 1 H), 7.67(dd, J=8.2, 2.2 Hz, 1 H), 7.58 (d, J=8.8 Hz, 1 H), 7.43-7.46 (m, 2 H),7.41 (dd, J=8.3, 2.2 Hz, 1 H), 7.31 (d, J=8.2 Hz, 1 H), 7.14 (d, J=15.4Hz, 1 H), 6.77 (d, J=15.4 Hz, 1 H), 5.00 (dd, J=9.9, 4.4 Hz, 1 H), 3.75(s, 3 H), 2.56-2.67 (m, 2 H), 2.21-2.30 (m, 1 H), 2.03-2.13 (m, 1 H),1.66-1.76 (m, 1 H), 1.25-1.57 (m, 7 H), 0.47-0.60 (m, 2H). MS (ESI) m/z:575.5 (M+H)⁺. Analytical HPLC: RT=5.73 min.

EXAMPLE 27{(Z)—(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-17,19-diaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 27 was prepared following the procedures described in step 2D,by replacing 2C with 10B and by replacing pent-4-enylboronic acid withhex-5-enylboronic acid; followed by steps 2F; 1F, by replacing ethanolwith methanol and running the reaction at 50-75° C.; and 1G. ¹H NMR (500MHz, CD₃OD) δ ppm 9.52 (s, 1 H), 7.98 (d, J=2.2 Hz, 1 H), 7.67 (dd,J=8.2, 2.2 Hz, 1 H), 7.58 (d, J=8.2 Hz, 1 H), 7.44 (s, 1 H), 7.41 (dd,J=8.3, 4.7 Hz, 1 H), 7.32 (s, 1 H), 7.30 (d, J=8.2 Hz, 1 H), 7.16 (d,J=15.4 Hz, 1 H), 6.78 (d, J=15.4 Hz, 1 H), 5.33-5.48 (m, 2 H), 5.10-5.17(m, 1 H), 3.74 (s, 3 H), 2.71-2.97 (m, 3 H), 2.44-2.61 (m, 1 H),1.99-2.23 (m, 2 H), 1.48-1.58 (m, 2 H), 0.99-1.25 (m, 2 H). MS (ESI)m/z: 573.5 (M+H)⁺. Analytical HPLC: RT=5.67 min.

EXAMPLE 28{(S)-18-Chloro-15-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-17,19-diaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 28 was prepared following the procedure described in 7, byreplacing Example 6 with Example 26. ¹H NMR (500 MHz, 50° C., CD₃OD) δppm 9.45 (s, 1 H), 7.95 (d, J=2.2 Hz, 1 H), 7.64 (dd, J=8.8, 2.2 Hz, 1H), 7.55 (d, J=8.2 Hz, 1 H), 7.40 (d, J=2.2 Hz, 1 H), 7.35 (dd, J=8.2,2.2 Hz, 1 H), 7.25 (d, J=8.2 Hz, 1 H), 7.13 (d, J=15.4 Hz, 1 H), 6.75(d, J=15.9 Hz, 1 H), 4.90 (dd, J=9.9, 4.4 Hz, 1H), 3.75 (s, 3H),2.62-2.73 (m, 1 H), 2.35-2.45 (m, 1 H), 2.07-2.16 (m, 1 H), 1.89-1.99(m, 1 H), 1.56-1.67 (m, 1 H), 1.22-1.45 (m, 7 H), 0.72-0.86 (m, 1 H),0.47-0.58 (d, 1 H). MS (ESI) m/z: 609.1 (M+H)⁺. Analytical HPLC: RT=7.81min.

EXAMPLE 29{(E)-(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8-oxa-17,19-diaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 29 was prepared following the procedures described in step 2A,by replacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate 11;followed by steps 2B; 2C; 2E; 1F, by replacing ethanol with methanol andrunning the reaction at 75° C.; and 1G. ¹H NMR (500 MHz, CD₃OD) δ ppm9.52 (s, 1 H), 7.99 (d, J=2.2 Hz, 1 H), 7.68 (dd, J=8.2, 2.2 Hz, 1 H),7.59 (d, J=8.2 Hz, 1 H), 7.46 (s, 1 H), 7.42 (s, 1 H), 7.37 (d, J=8.2Hz, 1 H), 7.17 (d, J=15.4 Hz, 1 H), 7.05 (dd, J=8.3, 1.6 Hz, 1 H), 6.79(d, J=15.4 Hz, 1 H), 5.66-5.74 (m, 1 H), 5.48-5.56 (m, 1 H), 5.11 (dd,J=10.2, 3.6 Hz, 1 H), 4.09-4.16 (m, 2 H), 3.75 (s, 3 H), 2.69-2.77 (m, 1H), 2.52-2.61 (m, 1 H), 2.33-2.47 (m, 2 H), 2.01-2.09 (m, 1 H),1.91-2.00 (m, 1 H). MS (ESI) m/z: 575.0 (M+H)⁺. Analytical HPLC: RT=6.15min.

EXAMPLE 30{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acroyolamino]-8-oxa-17,19-diaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 30 was prepared following the procedures described in step 2A,by replacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate 11;followed by steps 2B; 2C; 2E/2F; 2G; 1F, by replacing ethanol withmethanol and running the reaction at 75° C.; and 1G. ¹H NMR (500 MHz,CD₃OD) δ ppm 9.52 (s, 1 H), 7.97 (d, J=2.2 Hz, 1 H), 7.67 (dd, J=8.8,2.2 Hz, 1 H), 7.58 (d, J=8.8 Hz, 1 H), 7.40 (s, 1H), 7.33-7.38 (m, 2 H),7.14 (d, J=15.4 Hz, 1 H), 7.06 (d, J=8.2 Hz, 1 H), 6.78 (d, J=15.9 Hz, 1H), 5.04 (dd, J=9.9, 4.4 Hz, 1 H), 4.05-4.10 (m, 1 H), 3.93 (td, J=8.2,2.7 Hz, 1 H), 3.75 (s, 3 H), 2.19-2.27 (m, 1 H), 1.94-2.03 (m, 1 H),1.69-1.83 (m, 2 H), 1.49-1.63 (m, 4 H), 0.91-1.09 (m, 2 H). MS (ESI)m/z: 577.1 (M+H)⁺. Analytical HPLC: RT=6.16 min.

EXAMPLE 31{(Z)—(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8-oxa-17,19-diaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 31 was prepared following the procedures described in step 2A,by replacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate 11;followed by steps 2B; 2C; 2F; 1F, by replacing ethanol with methanol andrunning the reaction at 75° C.; and 1G. ¹H NMR (500 MHz, CD₃OD) δ ppm9.52 (s, 1 H), 7.97 (d, J=2.2 Hz, 1 H), 7.68 (dd, J=8.3, 2.2 Hz, 1 H),7.59 (d, J=8.2 Hz, 1 H), 7.50 (d, J=1.6 Hz, 1 H), 7.44 (s, 1 H), 7.38(d, J=8.2 Hz, 1 H), 7.15-7.21 (m, 2 H), 6.74 (d, J=15.9 Hz, 1 H),5.41-5.51 (m, 2 H), 5.20-5.25 (m, 1 H), 3.74-3.82 (m, 4 H), 3.66-3.72(m, 1 H), 2.95-3.06 (m, 1 H), 2.79-2.89 (m, 1 H), 2.47-2.58 (m, 1 H),2.23-2.34 (m, 1 H), 1.89-2.03 (m, 1 H), 1.65-1.77 (m, 1 H). MS (ESI)m/z: 575.1 (M+H)⁺. Analytical HPLC: RT=5.94 min.

EXAMPLE 32{(S)-18-Chloro-15-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8-oxa-17,19-diaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 32 was prepared following the procedure described in 9, byreplacing Example 8 with Example 30. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.46(s, 1 H), 7.94 (d, J=2.2 Hz, 1 H), 7.64 (dd, J=8.3, 2.2 Hz, 1 H), 7.55(d, J=8.8 Hz, 1 H), 7.32-7.37 (m, 2 H), 7.15 (d, J=15.9 Hz, 1 H), 7.05(d, J=8.2 Hz, 1 H), 6.74 (d, J=15.4 Hz, 1 H), 4.94 (dd, J=9.6, 3.6 Hz, 1H), 4.00-4.06 (m, 1 H), 3.88-3.94 (m, 1 H), 3.76 (s, 3 H), 2.12-2.20 (m,1 H), 1.75-1.93 (m, 2 H), 1.65-1.74 (m, 1 H), 1.46-1.60 (m, 4 H),1.0-1.12 (m, 1 H), 0.92-1.02 (m, 1 H). MS (ESI) m/z: 610.9 (M+H)⁺.Analytical HPLC: RT=7.74 min.

EXAMPLE 33{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8-methyl-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

Example 33 was prepared following the procedures described in step 10C,by replacing ammonium hydroxide with pent-4-enylamine and running thereaction at 90° C.; followed by steps 2E/2F; 2G (N-methylation occurredduring the hydrogenation step in the presence of methanol); 1F, byreplacing ethanol with methanol and running the reaction at 75° C.; and1G. ¹H NMR (500 MHz, 50° C., CD₃OD) δ ppm 9.52 (s, 1 H), 7.96 (d, J=2.2Hz, 1 H), 7.63-7.71 (m, 2 H), 7.55-7.60 (m, 2 H), 7.46 (d, J=8.2 Hz, 1H), 7.28 (dd, J=8.3, 2.2 Hz, 1 H), 7.14 (d, J=15.4 Hz, 1 H), 6.73 (d,J=15.4 Hz, 1H), 5.08 (t, J=6.9 Hz, 1 H), 3.76 (s, 3 H), 2.94 (s, 3 H),2.87-2.92 (m, 2H), 2.15-2.22 (m, 2H), 1.66-1.85 (m, 2 H), 1.39-1.65 (m,4 H), 0.75-0.87 (m, 2 H). MS (ESI) m/z: 590.3 (M+H)⁺. Analytical HPLC:RT=6.26 min.

EXAMPLE 34{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 34 was prepared following the procedures described in step 10D,by replacing but-3-enoic acid with pent-4-enoic acid; followed by steps2E/2F; 2G; 1F, by replacing ethanol with methanol and running thereaction at 75° C.; and 1G. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.50 (s, 1 H),7.96 (d, J=2.2 Hz, 1 H), 7.67 (dd, J=8.8, 2.2 Hz, 1 H), 7.61 (s, 1 H),7.57 (d, J=8.2 Hz, 1 H), 7.38-7.45 (m, 3 H), 7.12 (d, J=15.9 Hz, 1 H),6.74 (d, J=15.9 Hz, 1 H), 5.01 (dd, J=10.2, 4.7 Hz, 1 H), 3.75 (s, 3 H),2.28-2.41 (m, 2 H), 2.15-2.25 (m, 1 H), 1.95-2.07 (m, 1 H), 1.41-1.76(m, 4 H), 0.71-0.98 (m, 2 H). MS (ESI) m/z: 590.1 (M+H)⁺. AnalyticalHPLC: RT=4.96 min.

EXAMPLE 35{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

Example 35 was prepared following the procedures described in step 10C,by replacing ammonium hydroxide with pent-4-enylamine and running thereaction at 90° C.; followed by steps 2E/2F; 2G by replacing MeOH withEtOAc; 1F, by replacing ethanol with methanol and running the reactionat 75° C.; and 1G. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.52 (s, 1 H), 7.95 (d,J=2.2 Hz, 1 H), 7.82 (s, 1 H), 7.66 (dd, J=8.2, 2.2 Hz, 1 H), 7.60 (d,J=8.8 Hz, 1 H), 7.56-7.59 (m, 2 H), 7.26 (dd, J=8.8, 2.2 Hz, 1 H), 7.16(d, J=15.4 Hz, 1 H), 6.68 (d, J=15.9 Hz, 1 H), 5.12 (dd, J=9.9, 3.3 Hz,1 H), 3.76 (s, 3 H), 3.09-3.24 (m, 2 H), 2.31-2.43 (m, 1 H), 1.89-2.10(m, 2 H), 1.53-1.85 (m, 5 H), 1.07-1.27 (m, 2 H). MS (ESI) m/z: 576.3(M+H)⁺. Analytical HPLC: RT=5.91 min.

EXAMPLE 36{(E)-(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

Example 36 was prepared following the procedures described in step 10C,by replacing ammonium hydroxide with pent-4-enylamine and running thereaction at 90° C.; followed by steps 2E; 1F, by replacing ethanol withmethanol and running the reaction at 75° C.; and 1G. ¹H NMR (400 MHz,CD₃OD) δ ppm 9.52 (s, 1 H), 7.98 (d, J=2.2 Hz, 1 H), 7.68 (dd, J=8.8,2.2 Hz, 1 H), 7.59 (d, J=8.8 Hz, 1 H), 7.43 (s, 1 H), 7.28-7.32 (m, 2H), 7.18 (d, J=15.4 Hz, 1 H), 6.98 (dd, J=8.8, 2.2 Hz, 1 H), 6.76 (d,J=15.9 Hz, 1H), 5.69-5.79 (m, 1 H), 5.45-5.54 (m, 1 H), 5.15 (dd, J=9.3,4.4 Hz, 1 H), 3.74 (s, 3 H), 3.03-3.20 (m, 2 H), 2.72-2.82 (m, 1 H),2.56-2.68 (m, 1 H), 2.28-2.48 (m, 2 H), 1.82-2.03 (m, 2 H). MS (ESI)m/z: 574.2 (M+H)⁺. Analytical HPLC: RT=5.85 min.

EXAMPLE 37{(Z)—(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

Example 37 was prepared following the procedures described in step 10C,by replacing ammonium hydroxide with pent-4-enylamine and running thereaction at 90° C.; followed by steps 2F; 1F, by replacing ethanol withmethanol and running the reaction at 75° C.; and 1G. ¹H NMR (500 MHz,CD₃OD) δ ppm 9.48 (s, 1 H), 7.86-7.95 (m, 2 H), 7.69 (d, J=8.2 Hz, 1 H),7.65 (dd, J=8.8, 2.2 Hz, 1 H), 7.54-7.58 (m, 2 H), 7.33 (dd, J=8.2, 2.2Hz, 1 H), 7.21 (d, J=15.9 Hz, 1 H), 6.65 (d, J=15.9 Hz, 1 H), 5.52-5.60(m, 1 H), 5.36-5.44 (m, 1 H), 5.30 (dd, J=9.9, 3.3 Hz, 1 H), 3.78 (s, 3H), 3.10-3.28 (m, 3 H), 2.60-2.76 (m, 2 H), 2.36-2.47 (m, 1 H),2.15-2.25 (m, 1 H), 1.96-2.07 (m, 1 H). MS (ESI) m/z: 574.2 (M+H)⁺.Analytical HPLC: RT=5.88 min.

EXAMPLE 38{(S)-18-Chloro-15-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 38 was prepared following the procedure described in 7, byreplacing Example 6 with Example 34. ¹H NMR (500 MHz, DMSO-d₆+2 drops ofD₂O) δ ppm 9.76 (s, 1 H), 7.90 (d, J=1.6 Hz, 1 H), 7.67 (dd, J=8.8, 2.2Hz, 1 H), 7.63 (d, J=8.3 Hz, 1 H), 7.38 (s, 1 H), 7.30-7.36 (m, 2 H),6.77-6.84 (m, 2 H), 4.76 (dd, J=10.4, 4.4 Hz, 1 H), 3.62 (s, 3 H),2.07-2.21 (m, 2 H), 1.83-1.91 (m, 1 H), 1.56-1.66 (m, 1 H), 1.44-1.54(m, 1 H), 1.34-1.44 (m, 1 H), 1.19-1.31 (m, 2 H), 0.85-0.96 (m, 1 H),0.38-0.49 (m, 1 H). MS (ESI) m/z: 624.3 (M+H)⁺. Analytical HPLC: RT=6.32min.

EXAMPLE 39{(E)-(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamic acid methyl ester, 1 TFA salt

39A.((E)-(S)-15-tert-Butoxycarbonylamino-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl)-carbamicacid methyl ester: This compound was prepared following the proceduresdescribed in step 10D, by replacing but-3-enoic acid with pent-4-enoicacid; followed by step 2E. MS (ESI) m/z: 586.4 (M+H)⁺.

39B. Example 39 was prepared following the procedures described step10H, by replacing 10G with 39A; followed by step 1G. ¹H NMR (500 MHz,CD₃OD) δ ppm 9.51 (s, 1 H), 7.97 (d, J=2.2 Hz, 1 H), 7.68 (dd, J=8.5,2.5 Hz, 1 H), 7.58 (d, J=8.2 Hz, 2 H), 7.37-7.41 (m, 3 H), 7.14 (d,J=15.4 Hz, 1 H), 6.76 (d, J=15.4 Hz, 1 H), 5.50-5.59 (m, 1 H), 5.37-5.45(m, 1 H), 5.08 (dd, J=10.2, 4.7 Hz, 1 H), 3.75 (s, 3 H), 2.76-2.84 (m, 1H), 2.32-2.60 (m, 5 H). MS (ESI) m/z: 588.1 (M+H)⁺. Analytical HPLC:RT=4.79 min

EXAMPLE 40{(E)-(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-10-oxa-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 40 was prepared following the procedures described inIntermediate 7B, by replacing Intermediate 7A with 10C and by replacingmethyl chloroformate with allyl chloroformate; followed by steps 2E;10H; and 1G. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.50 (s, 1 H), 7.98 (d, J=2.2Hz, 1 H), 7.68 (dd, J=8.5, 2.5 Hz, 1H), 7.58 (d, J=8.5 Hz, 1 H), 7.50(br. s., 1 H), 7.34-7.43 (m, 3 H), 7.14 (d, J=15.7 Hz, 1 H), 6.76 (d,J=15.7 Hz, 1 H), 5.83-5.93 (m, 1 H), 5.68-5.76 (m, 1 H), 5.13 (dd,J=10.2, 5.2 Hz, 1 H), 4.28-4.43 (m, 2 H), 3.75 (s, 3 H), 2.88-2.97 (m, 1H), 2.53-2.65 (m, 1 H). MS (ESI) m/z: 590.2 (M+H)⁺. Analytical HPLC:RT=4.90 min.

EXAMPLE 41{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-10-oxa-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 41 was prepared following the procedures described inIntermediate 7B, by replacing Intermediate 7A with 10C and by replacingmethyl chloroformate with allyl chloroformate; followed by steps 2E/2F;2G, by replacing methanol with EtOAc; 1F, by replacing ethanol withmethanol and running the reaction at 75° C. for 2 h; and 1 G. ¹H NMR(400 MHz, CD₃OD) δ ppm 9.50 (s, 1 H), 7.96 (d, J=2.2 Hz, 1 H), 7.68 (dd,J=8.8, 2.2 Hz, 1 H), 7.58 (d, J=8.2 Hz, 1 H), 7.55 (d, J=1.6 Hz, 1 H),7.43-7.47 (m, 2 H), 7.39 (dd, J=8.3, 2.2 Hz, 1 H), 7.12 (d, J=15.4 Hz, 1H), 6.74 (d, J=15.4 Hz, 1 H), 4.98 (dd, J=10.4, 4.9 Hz, 1 H), 4.13-4.26(m, 1 H), 3.89-4.03 (m, 1 H), 3.75 (s, 3 H), 2.18-2.31 (m, 1 H),1.84-1.98 (m, 1 H), 1.42-1.65 (m, 3 H), 1.19-1.35 (m, 1 H). MS (ESI)m/z: 592.2 (M+H)⁺. Analytical HPLC: RT=5.11 min.

EXAMPLE 42{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-11-methyl-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt. Mixture of diastereomers

Example 42 (mixture of diastereomers) was prepared following theprocedures described in step 10D, by replacing but-3-enoic acid with3-methylpent-4-enoic acid; followed by steps 2E/2F; 2G; 10H; and 1 G. ¹HNMR (500 MHz, CD₃OD) δ ppm 9.50, 9.51 (s, 1 H), 7.94-7.98 (m, 1 H),7.64-7.69 (m, 1 H), 7.55-7.60 (m, 2 H), 7.37-7.44 (m, 3 H), 7.08-7.15(m, 1 H), 6.70-6.82 (m, 1 H), 4.96-5.02 (m, 1 H), 3.75 (s, 3 H),2.38-2.47 (m, 1 H), 2.19-2.26 (m, 0.5 H), 2.10-2.18 (m, 0.5 H),1.87-2.07 (m, 3 H), 1.54-1.70 (m, 1 H), 1.36-1.52 (m, 1 H), 0.95-1.02(m, 3.5 H), 0.80-0.89 (m, 0.5 H), 0.67-0.77 (m, 0.5 H), 0.46-0.55 (m,0.5 H). MS (ESI) m/z: 604.3 (M+H)⁺. Analytical HPLC: RT=5.11 min.

EXAMPLE 43{(11S,15S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-11-methyl-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamic acid methyl ester, 1 TFA salt; and EXAMPLE44 {(11R,15S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-11-methyl-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamic acid methyl ester, 1 TFA salt

The diastereomers of Example 42 were separated on CHIRALCEL® OD-H column(isocratic; 30% 1:1 MeOH:EtOH/Heptane; 20 mL/min; 254 nm detection). Thepure fractions were concentrated, dissolved in methanol containing twodrops of TFA, concentrated and then lyophilized to give 0.0047 g ofExample 43, as a white solid and 0.0042 g of Example 44, as a whitesolid.

Example 43: ¹H NMR (500 MHz, CD₃OD) δ ppm 9.52 (s, 1 H), 7.98 (d, J=2.2Hz, 1 H), 7.68 (dd, J=8.8, 2.2 Hz, 1 H), 7.56-7.62 (m, 2 H), 7.37-7.44(m, 3 H), 7.14 (d, J=15.9 Hz, 1 H), 6.77 (d, J=15.9 Hz, 1 H), 5.00 (dd,J=9.3, 4.4 Hz, 1 H), 3.75 (s, 3 H), 2.43 (d, J=10.4 Hz, 1 H), 2.18-2.30(m, 1 H), 1.84-1.98 (m, 3 H), 1.61-1.74 (m, 1 H), 1.34-1.49 (m, 1 H),0.93-1.05 (m, 4 H), 0.46-0.58 (m, 1 H). MS (ESI) m/z: 604.3 (M+H)⁺ and606.2 (M+2+H)⁺. Analytical HPLC (Method D): RT=4.63 min. CHIRALCEL® OD(40% 1:1 MeOH:EtOH/Heptane; 4.6×250 mm; 1 mL/min.; 220 nm): 10.08 min.(>99% de).

Example 44: ¹H NMR (500 MHz, CD₃OD) □□δ ppm 9.60 (s, 1 H, exchangeable),9.50 (s, 1 H), 7.95 (d, J=1.6 Hz, 1 H), 7.66 (dd, J=8.2, 2.2 Hz, 1 H),7.59 (br. s., 1 H), 7.57 (d, J=8.8 Hz, 1 H), 7.36-7.45 (m, 3 H), 7.11(d, J=15.9 Hz, 1 H), 6.71 (d, J=15.9 Hz, 1 H), 4.98 (dd, J=10.4, 4.4 Hz,1 H), 3.75 (s, 3 H), 2.42 (d, J=11.0 Hz, 1 H), 2.08-2.19 (m, 1 H),1.91-2.08 (m, 3 H), 1.56-1.65 (m, 1 H), 1.41-1.52 (m, 1 H), 0.99 (d,J=6.6 Hz, 3 H), 0.81-0.94 (m, 1 H), 0.69-0.79 (m, 1 H). MS (ESI) m/z:604.3 (M+H)⁺ and 606.2 (M+2+H)⁺. Analytical HPLC (Method D): RT=4.69min. CHIRALCEL® OD (40% 1:1 MeOH:EtOH/Heptane; 4.6×250 mm; 1 mL/min.;220 nm): 13.74 min. (>99% de).

EXAMPLE 45{(E)-(S)-15-[(4-Aminomethyl-cyclohexanecarbonyl)-amino]-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

Example 45 was prepared following the procedures described in step 10H,by replacing 10G with 39A; followed by steps 3B, by replacing Hunig'sbase with triethylamine and running the reaction at 50° C.; and 3C. ¹HNMR (400 MHz, CD₃OD) δ ppm 7.55 (d, J=1.6 Hz, 1 H), 7.43 (dd, J=8.2, 2.2Hz, 1 H), 7.37-7.40 (m, 2 H), 5.46-5.56 (m, 1 H), 5.34-5.43 (m, 1 H),4.98 (dd, J=10.4, 4.4 Hz, 1 H), 3.75 (s, 3 H), 2.71-2.82 (m, 3 H),2.27-2.55 (m, 6 H), 1.83-1.99 (m, 4 H), 1.56-1.67 (m, 1 H), 1.39-1.53(m, 2 H), 1.01-1.17 (m, 2 H). MS (ESI) m/z: 495.3 (M+H)⁺. AnalyticalHPLC: RT=1.8, 2.4 min.

EXAMPLE 46{(S)-4,18-Dichloro-15-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

To a solution of Example 34 (0.023 g, 0.033 mmol) in acetonitrile (1mL)/chloroform (1.000 mL) was added NCS (5.23 mg, 0.039 mmol). Thethick-walled vial was sealed with a teflon coated screw cap and thereaction was warmed to 65° C. After 6 h, additional NCS (5.23 mg, 0.039mmol) was added. After another 4 h, the reaction was cooled to rt andconcentrated. Purification by reverse phase chromatography affordedExample 46 (0.006 g, 23.2%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δppm 9.50 (s, 1 H), 7.93-8.02 (m, 2 H), 7.62-7.68 (m, 1 H), 7.53-7.59 (m,2 H), 7.10 (d, J=15.4 Hz, 1 H), 6.75 (d, J=15.4 Hz, 1 H), 4.79-4.98 (m,1 H), 3.78 (s, 3 H), 2.26-2.37 (m, 2 H), 2.01-2.12 (m, 1 H), 1.84-1.95(m, 1 H), 1.59-1.72 (m, 2 H), 1.32-1.50 (m, 2 H), 1.05-1.19 (m, 1 H),0.73-0.86 (m, 1 H). MS (ESI) m/z: 656.4 (M−H)⁻. Analytical HPLC: RT=7.49min.

EXAMPLE 47{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-12-methyl-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 47 was prepared following the procedures described in step 10D,by replacing but-3-enoic acid with 4-methylpent-4-enoic acid; followedby steps 2E/2F; 10H; and 1G. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.52 (s, 1H), 7.99 (d, J=2.2 Hz, 1 H), 7.69 (dd, J=8.8, 2.2 Hz, 1 H), 7.55-7.62(m, 2 H), 7.33-7.44 (m, 3 H), 7.15 (d, J=15.9 Hz, 1 H), 6.78 (d, J=15.9Hz, 1 H), 5.14-5.21 (m, 1 H), 5.06 (dd, J=10.2, 5.2 Hz, 1 H), 3.76 (s, 3H), 2.75-2.83 (m, 1 H), 2.48-2.69 (m, 3 H), 2.34-2.42 (m, 2 H), 1.56 (s,3 H). MS (ESI) m/z: 602.3 (M+H)⁺. Analytical HPLC: RT=5.09 min.

EXAMPLE 48(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((Z)-(S)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-acrylamide,1 TFA salt

Example 48 was prepared following the procedures described in step 10D,by replacing 10C with 15B and by replacing but-3-enoic acid withpent-4-enoic acid; followed by 2F; 10H; and 15D. ¹H NMR (500 MHz, CD₃OD)δ ppm 2.25-3.00 (m, 6H), 5.14-5.24 (m, 1 H), 5.41-5.54 (m, 1 H),5.57-5.70 (m, 1 H), 6.75 (d, J=15.7 Hz, 1 H), 7.17 (d, J=15.7 Hz, 1 H),7.33-7.40 (m, 3 H), 7.48-7.54 (m, 2 H), 7.58 (d, J=8.5 Hz, 1 H), 7.67(dd, J=8.5, 2.2 Hz, 1 H), 7.98 (d, J=2.2 Hz, 1 H), 9.51 (s, 1 H). MS(ESI) m/z: 515.3(M+H)⁺. Analytical HPLC: RT=5.06 min.

EXAMPLE 49(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((E)-(S)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-acrylamide,1 TFA salt

Example 49 was prepared following the procedures described in step 10D,by replacing 10C with 15B and by replacing but-3-enoic acid withpent-4-enoic acid; followed by steps 2E; 10H; and 15D. ¹H NMR (500 MHz,CD₃OD) δ ppm 2.32-2.62 (m, 5 H), 2.77-2.86 (m, 1 H), 5.09 (dd, J=10.2,4.7 Hz, 1 H), 5.38-5.47 (m, 1 H), 5.52-5.61 (m, 1 H), 6.76 (d, J=15.4Hz, 1 H), 7.15 (d, J=15.4 Hz, 1 H), 7.34 (dd, J=8.0, 0.8 Hz, 1 H), 7.41(td, J=7.6, 1.2 Hz, 1 H), 7.44 (s, 1 H), 7.52 (dd, J=7.7, 1.4 Hz, 1 H),7.55 (td, J=7.7, 1.6 Hz, 1 H), 7.59 (d, J=8.5 Hz, 1 H), 7.68 (dd, J=8.5,2.5 Hz, 1 H), 7.98 (d, J=2.2 Hz, 1 H), 9.51 (s, 1 H). MS (ESI) m/z:515.3(M+H)⁺. Analytical HPLC: RT=5.00 min.

EXAMPLE 50(E)-N-((E)-(S)-18-Chloro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylamide,1 TFA salt

Example 50 was prepared following the procedure described in 17A, byreplacing 16A with Example 49. ¹H NMR (500 MHz, CD₃OD) δ ppm 2.30-2.53(m, 5H), 2.66-2.76 (m, 1 H), 4.97 (dd, J=10.3, 4.3 Hz, 1 H), 5.32-5.42(m, 1 H), 5.49-5.59 (m, 1 H), 6.77 (d, J=15.7 Hz, 1 H), 7.14 (d, J=15.7Hz, 1 H), 7.32 (dd, J=7.7, 1.2 Hz, 1 H), 7.40 (td, J=7.6, 1.3 Hz, 1 H),7.48-7.53 (m, 2 H), 7.58 (d, J=8.3 Hz, 1 H), 7.67 (dd, J=8.5, 2.2 Hz, 1H), 7.98 (d, J=2.2 Hz, 1 H), 9.51 (s, 1 H). MS (ESI) m/z: 549.2(M+H)⁺.Analytical HPLC: RT=6.87 min.

EXAMPLE 51 4-Aminomethyl-cyclohexanecarboxylic acid((E)-(S)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-amide,2 TFA salt

Example 51 was prepared following the procedures described in step 10D,by replacing 10C with 15B and by replacing but-3-enoic acid withpent-4-enoic acid; followed by steps 2E; 10H; 3B; and 3C. ¹H NMR (500MHz, CD₃OD) δ ppm 1.03-1.17 (m, 2 H), 1.40-1.53 (m, 2 H), 1.56-1.67 (m,1 H), 1.83-2.00 (m, 4 H), 2.29-2.45 (m, 4 H), 2.45-2.55 (m, 2 H),2.72-2.81 (m, 3 H), 5.00 (dd, J=10.6, 4.8 Hz, 1 H), 5.35-5.44 (m, 1 H),5.47-5.56 (m, 1 H), 7.33 (dd, J=8.0, 0.8 Hz, 1 H), 7.42 (td, J=7.6, 1.3Hz, 1 H), 7.44 (s, 1 H), 7.50 (dd, J=7.7, 1.7 Hz, 1 H), 7.55 (td, J=7.7,1.7 Hz, 1 H). MS (ESI) m/z: 422.3(M+H)⁺. Analytical HPLC: RT=1.62 min.

EXAMPLE 52{(R)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-13-oxa-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

52A. (S)-3-Allyloxy-2-tert-butoxycarbonylamino-propionic acid methylester: This compound was prepared following a procedure described inOrganic Letters, 10(17):3883 (2008). To a solution ofN-(tert-butoxycarbonyl)-L-serine methyl ester (0.781 mL, 3.85 mmol) inTHF (15 mL) was added allyl methyl carbonate (0.524 mL, 4.61 mmol). Thesolution was purged with N₂, followed by the addition oftetrakis(triphenylphosphine)palladium(0) (444 mg, 0.385 mmol). Thevessel was sealed and heated at 60° C. overnight. The reaction mixturewas diluted with ethyl acetate, washed with sat NaHCO₃, and brine. Theorganic layer was concentrated. Purification by normal phasechromatography provided 52A (550 mg, 55.2% yield) as a yellow oil. ¹HNMR (400 MHz, CDCl₃) δ ppm 5.75-5.94 (m, 1 H) 5.32-5.47 (m, 1 H)5.11-5.29 (m, 2 H) 4.35-4.53 (m, 1 H) 3.92-4.03 (m, 2 H) 3.80-3.89 (m, 1H) 3.76 (m, 3 H) 3.61-3.70 (m, 1 H) 1.46 (m, 9 H).

52B. (S)-3-Allyloxy-2-tert-butoxycarbonylamino-propionic acid: Asolution of 52A (1000 mg, 3.86 mmol) and lithium hydroxide (486 mg,11.57 mmol) in THF, water and MeOH was stirred at rt for 4 h. Thesolution was acidified using 5M HCl in water (pH˜3). The mixture wasextracted with EtOAc. The combined organic layers were concentrated togive 52B (0.96 g, 100% yield) as a yellow oil. MS (ESI) m/z: 146.0(M+H-boc)⁺.

52C. (S)-3-Allyloxy-2-tert-butoxycarbonylamino-propionic acid2-(2-bromo-4-nitro-phenyl)-2-oxo-ethyl ester: To a solution of 52B (0.95g, 3.87 mmol) and Intermediate 10 (1.376 g, 4.26 mmol) in DMF (20 mL)was added potassium bicarbonate (0.465 g, 4.65 mmol). After 1.5 h at rt,the reaction was diluted with EtOAc, washed with water, saturated sodiumbicarbonate solution, then brine, dried over magnesium sulfate,filtered, and concentrated to give 52C (1.82 g, 96% yield) as a thickorange oil. MS (ESI) m/z: 389.0(M+H-boc)⁺.

52D. (S)-3-Allyloxy-2-tert-butoxycarbonylamino-propionic acid2-(4-amino-2-bromo-phenyl)-2-oxo-ethyl ester: To a mixture of 52C (1700mg, 3.49 mmol) and iron (3896 mg, 69.8 mmol) in ethanol (15 mL) andwater (15.00 mL) was added 12M conc. HCl (0.204 mL, 2.442 mmol). Thesuspension was heated at 50° for 2 hr. The dark suspension was filtered,washed with methanol and concentrated to give 52D (1.7 g, 100%). MS(ESI) m/z: 359.0(M+H-boc)⁺.

52E. (S)-3-Allyloxy-2-tert-butoxycarbonylamino-propionic acid2-(2-bromo-4-methoxycarbonylamino-phenyl)-2-oxo-ethyl ester: To a cooled(ice bath) solution 52D (1670 mg, 3.65 mmol) and pyridine (0.325 mL,4.02 mmol) in dichloromethane (50 mL) was added methyl chloroformate(0.297 mL, 3.83 mmol). The reaction mixture was stirred for 10 min,washed with brine, dried (MgSO₄) and concentrated to give 52E (1.8 g,96% yield) as a yellow foam. MS (ESI) m/z: 417.1(M+H-boc)⁺.

52F.{4-[2-((R)-2-Allyloxy-1-tert-butoxycarbonylamino-ethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-amino-phenyl}-carbamicacid methyl ester: This compound was prepared following the proceduresdescribed in step 1B, by replacing 1A with 52E; followed by steps 10B;and 10C (alternative). MS (ESI) m/z: 562.3(M+H)⁺.

52G.{3-Acryloylamino-4-[2-((R)-2-allyloxy-1-tert-butoxycarbonylamino-ethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: A solution of 52F (50 mg, 0.089 mmol), and DIEA (50μL, 0.286 mmol) in THF (2 mL) was cooled in ice bath. Acryloyl chloride(10 μL, 0.123 mmol) was added into the solution in a portion. Then, theice bath was removed and reaction mixture was stirred for 1 hr at rt. Tothe reaction mixture was added sat. NaHCO₃ and the mixture was extractedwith EtOAc. The combined organic layer were washed with brine andconcentrated to provide an oily residue, which has gel like materialinsoluble in CH₂Cl₂. The soluble portion of the residue was purified bynormal phase chromatography to give 52G (43 mg, 78% yield). MS(ESI) m/z:616.4 (M+H)⁺.

52H. Example 52 was prepared following the procedures described in step2E/2F, by replacing 2D with 52G; followed by steps 2G; 10H; and 1G. ¹HNMR (400 MHz, CDCl₃) δ ppm 8.94 (s, 1 H) 7.79 (s, 1 H) 7.50-7.62 (m, 1H) 7.42 (t, J=7.91 Hz, 2 H) 7.10 (br. s., 1 H) 6.60 (d, J=15.31 Hz, 1 H)5.22 (br. s., 1 H) 4.04-4.18 (m, 1 H) 3.92-4.02 (m, 1 H) 3.78 (s, 4 H)3.60 (d, J=6.27 Hz, 2 H) 3.28-3.49 (m, 1 H) 2.81 (t, J=7.28 Hz, 1 H)2.34 (s, 1 H) 2.05 (d, J=5.02 Hz, 2 H) 1.63 (br. s., 1 H) 0.88 (t,J=6.90 Hz, 2 H). MS(ESI) m/z: 592.3(M+H)⁺. Analytical HPLC: RT=5.16 min.

EXAMPLE 53(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((E)-(S)-11-methyl-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-acrylamide,1 TFA salt

53A.{(S)-1-[4-[2-(3-Methyl-pent-4-enoylamino)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-but-3-enyl}-carbamicacid tert-butyl ester: This compound was prepared following theprocedure described in 10D, by replacing 10C with 15B and by replacingbut-3-enoic acid with 3-methyl-4-pentenoic acid. MS (ESI) m/z:555.5(M+H)⁺.

53B.[(E)-(S)-11-Methyl-9-oxo-17-(2-trimethylsilanyl-ethoxymethyl)-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl]-carbamicacid tert-butyl ester, 1 TFA salt, diastereomer A; 53C.[(E)-(S)-11-Methyl-9-oxo-17-(2-trimethylsilanyl-ethoxymethyl)-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl]-carbamicacid tert-butyl ester, 1 TFA salt, diastereomer B; and 53D.[(Z)—(S)-11-Methyl-9-oxo-17-(2-trimethylsilanyl-ethoxymethyl)-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl]-carbamicacid tert-butyl ester, 1 TFA salt

These compounds were prepared following the procedure described in2E/2F, by replacing 2D with 53A. Purification by reverse phasechromatography gave 53B, diastereomer A (16.3 mg, 2.291% yield) as apale, purple foam; 53C, diastereomer B (180.6 mg, 25.4% yield) as apale, purple foam; and 53D (90.5 mg, 12.72% yield) as a pale, purplefoam.

53E. Example 53 was prepared following the procedures described in step10H, by replacing 10G with 53C; followed by step 15D. ¹H NMR (500 MHz,CD₃OD) δ ppm 1.06 (d, J=6.9 Hz, 3 H), 2.13 (dd, J=13.9, 11.7 Hz, 1 H),2.43-2.53 (m, 2 H), 2.65-2.77 (m, 1 H), 2.83-2.91 (m, 1 H), 5.05 (dd,J=11.8, 4.7 Hz, 1 H), 5.28 (ddd, J=15.1, 9.4, 1.1 Hz, 1 H), 5.53 (ddd,J=15.1, 10.5, 4.1 Hz, 1 H), 6.77 (d, J=15.7 Hz, 1 H), 7.17 (d, J=15.7Hz, 1 H), 7.34 (d, J=8.0 Hz, 1 H), 7.39-7.44 (m, 2 H), 7.51 (dd, J=7.7,1.4 Hz, 1 H), 7.56 (td, J=7.7, 1.4 Hz, 1 H), 7.59 (d, J=8.5 Hz, 1 H),7.69 (dd, J=8.5, 2.2 Hz, 1 H), 7.99 (d, J=2.2 Hz, 1 H), 9.52 (s, 1 H).MS (ESI) m/z: 529.3(M+H)⁺. Analytical HPLC: RT=5.39 min.

EXAMPLE 54 4-Aminomethyl-cyclohexanecarboxylic acid((E)-(S)-18-chloro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-amide,2 TFA salt

Example 54 was prepared following the procedures described in step 10D,by replacing 10C with 15B and by replacing but-3-enoic acid withpent-4-enoic acid; followed by steps 2E; 10H; 3B; 17A; and 3C. ¹H NMR(500 MHz, CD₃OD) δ ppm 1.02-1.18 (m, 2 H), 1.40-1.55 (m, 2 H), 1.56-1.68(m, 1 H), 1.84-1.98 (m, 4 H), 2.26-2.53 (m, 6 H), 2.68-2.76 (m, 1 H),2.79 (d, J=7.2 Hz, 2 H), 4.88-4.92 (m, 1 H), 5.33-5.43 (m, 1 H),5.46-5.55 (m, 1 H), 7.33 (dd, J=8.0, 0.8 Hz, 1 H), 7.43 (td, J=7.6, 1.1Hz, 1 H), 7.51 (dd, J=7.7, 1.4 Hz, 1 H), 7.55 (td, J=7.7, 1.6 Hz, 1 H).MS (ESI) m/z: 456.2(M+H)⁺. Analytical HPLC: RT=3.36 min.

EXAMPLE 55(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((Z)-(S)-11-methyl-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-acrylamide,1 TFA salt

Example 55 was prepared following the procedures described in step 10H,by replacing 10G with 53D; followed by step 15D. ¹H NMR (500 MHz, CD₃OD)δ ppm 1.06 (d, J=6.6 Hz, 3 H), 2.08 (t, J=12.0 Hz, 1 H), 2.47 (dd,J=12.4, 2.5 Hz, 1 H), 2.58-2.67 (m, 1 H), 2.83-2.96 (m, 1 H), 2.99-3.08(m, 1 H), 5.14 (dd, J=12.4, 4.4 Hz, 1 H), 5.33 (td, J=11.5, 3.4 Hz, 1H), 5.46-5.54 (m, 1 H), 6.74 (d, J=15.7 Hz, 1 H), 7.14 (d, J=15.4 Hz, 1H), 7.27 (d, J=8.0 Hz, 1 H), 7.36-7.42 (m, 2 H), 7.47-7.53 (m, 2 H),7.56 (d, J=8.5 Hz, 1 H), 7.65 (dd, J=8.5, 2.5 Hz, 1 H), 7.97 (d, J=2.2Hz, 1 H), 9.50 (s, 1 H). MS (ESI) m/z: 529.3(M+H)⁺. Analytical HPLC:RT=5.35 min.

EXAMPLE 56(E)-N-((E)-(S)-18-Chloro-11-methyl-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylamide,1 TFA salt

Example 56 was prepared following the procedure described in 17A, byreplacing 16A with Example 53. ¹H NMR (500 MHz, CD₃OD) δ ppm 1.05 (d,J=6.9 Hz, 3 H), 2.16 (dd, J=13.9, 11.7 Hz, 1 H), 2.30-2.39 (m, 1 H),2.42 (dd, J=13.9, 3.2 Hz, 1 H), 2.64-2.79 (m, 2 H), 4.92 (dd, J=11.8,4.1 Hz, 1 H), 5.19 (ddd, J=15.1, 9.4, 1.1 Hz, 1 H), 5.52 (ddd, J=14.9,10.7, 4.1 Hz, 1 H), 6.79 (d, J=15.7 Hz, 1 H), 7.15 (d, J=15.7 Hz, 1 H),7.32 (dd, J=7.8, 1.0 Hz, 1 H), 7.40 (td, J=7.6, 1.2 Hz, 1 H), 7.47 (dd,J=7.7, 1.4 Hz, 1 H), 7.51 (td, J=7.7, 1.5 Hz, 1 H), 7.58 (d, J=8.5 Hz, 1H), 7.67 (dd, J=8.5, 2.2 Hz, 1 H), 8.01 (d, J=2.5 Hz, 1 H), 9.52 (s, 1H). MS (ESI) m/z: 563.3(M+H)⁺. Analytical HPLC: RT=7.22 min.

EXAMPLE 57(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((E)-(S)-11-methyl-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-acrylamide,1 TFA salt

Example 57 was prepared following the procedures described in step 10H,by replacing 10G with 53B; followed by step 15D. ¹H NMR (500 MHz, CD₃OD)δ ppm 1.08 (d, J=6.9 Hz, 3 H), 2.26 (dd, J=14.3, 11.6 Hz, 1 H), 2.49(dd, J=14.4, 3.7 Hz, 1 H), 2.63-2.75 (m, 3 H), 5.18 (dd, J=6.7, 5.4 Hz,1 H), 5.44 (dd, J=15.5, 8.7 Hz, 1 H), 5.55-5.64 (m, 1 H), 6.76 (d,J=15.4 Hz, 1 H), 7.14 (d, J=15.7 Hz, 1 H), 7.31 (d, J=8.0 Hz, 1 H), 7.40(td, J=7.6, 1.1 Hz, 1 H), 7.48 (s, 1 H), 7.50-7.56 (m, 2 H), 7.58 (d,J=8.5 Hz, 1 H), 7.68 (dd, J=8.5, 2.2 Hz, 1 H), 7.96 (d, J=2.2 Hz, 1 H),9.50 (s, 1 H). MS (ESI) m/z: 529.3(M+H)⁺. Analytical HPLC: RT=6.03 min.

EXAMPLE 58(E)-N-((Z)-(S)-18-Chloro-11-methyl-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylamide,1 TFA salt

Example 58 was prepared following the procedure described in 17A, byreplacing 16A with Example 55. ¹H NMR (500 MHz, CD₃OD) δ ppm 1.06 (d,J=6.9 Hz, 3 H), 2.16 (t, J=12.1 Hz, 1 H), 2.40 (dd, J=12.8, 2.3 Hz, 1H), 2.54-2.63 (m, 1 H), 2.81-2.96 (m, 2 H), 4.97 (dd, J=12.0, 4.3 Hz, 1H), 5.35 (td, J=11.5, 3.4 Hz, 1 H), 5.50 (td, J=10.6, 1.7 Hz, 1 H), 6.71(d, J=15.7 Hz, 1 H), 7.16 (d, J=15.7 Hz, 1 H), 7.30 (dd, J=8.0, 0.8 Hz,1 H), 7.39 (td, J=7.6, 1.3 Hz, 1 H), 7.50 (td, J=7.8, 1.5 Hz, 1 H), 7.54(dd, J=7.7, 1.4 Hz, 1 H), 7.57 (d, J=8.5 Hz, 1 H), 7.66 (dd, J=8.5, 2.2Hz, 1 H), 7.97 (d, J=2.2 Hz, 1 H), 9.51 (s, 1 H). MS (ESI) m/z:563.3(M+H)⁺. Analytical HPLC: RT=6.93 min.

EXAMPLE 59(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((S)-11-methyl-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-15-yl)-acrylamide, 1 TFA salt

Example 59 was prepared following the procedures described in step 2G,by replacing 2E/2F with a mixture of 53B and 53C and by replacing thehydrogen balloon with hydrogen (50 psi); followed by steps 10H; and 15D.MS (ESI) m/z: 531.3(M+H)⁺. Analytical HPLC: RT=5.79 min.

EXAMPLE 60(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((S)-11-methyl-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-15-yl)-acrylamide,1 TFA salt

Example 60 was prepared following the procedures described in step 2G,by replacing 2E/2F with 53C and by replacing the hydrogen balloon withhydrogen (50 psi); followed by steps 10H; and 15D. ¹H NMR (500 MHz,CD₃OD) δ ppm 0.48-0.60 (m, 1 H), 0.98-1.02 (m, 4 H), 1.34-1.49 (m, 1 H),1.58-1.74 (m, 1 H), 1.86-2.02 (m, 3 H), 2.22-2.29 (m, 1 H), 2.40-2.47(m, 1 H), 5.00 (dd, J=9.6, 4.4 Hz, 1 H), 6.77 (d, J=15.7 Hz, 1 H), 7.14(d, J=15.7 Hz, 1 H), 7.33 (dd, J=8.0, 0.8 Hz, 1 H), 7.41-7.47 (m, 2 H),7.51-7.60 (m, 3 H), 7.68 (dd, J=8.5, 2.2 Hz, 1 H), 7.97 (d, J=2.2 Hz, 1H), 9.50 (s, 1 H). MS (ESI) m/z: 531.3(M+H)⁺. Analytical HPLC: RT=5.01min.

EXAMPLE 61{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-12-methyl-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt, diastereomer A; and EXAMPLE 62{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-12-methyl-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester 1 TFA salt, diastereomer B

61A. (S)-MethylN-4-(2-(1-(tert-butoxycarbonylamino)but-3-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-(4-methylpent-4-enamido)phenylmethanimidoperoxoate:This compound was prepared following the procedure described in 10D, byreplacing but-3-enoic acid with 4-methylpent-4-enoic acid. MS (ESI) m/z:628.2 (M+H)⁺.

61B. To a solution of 61A (0.066 g, 0.105 mmol) in DCE (1 mL) was addedGrubbs (II) (0.018 g, 0.021 mmol). The reaction mixture was vacuumed andback-filled with argon three times, and then the microwave vial wascapped. The reaction was microwaved at 120° C. for 20 min, cooled to rtand concentrated. Purification by reverse phase chromatography afforded61B (mixture of E/Z isomers) (0.026 g, 34.6%) as a brown solid. MS (ESI)m/z: 600.5 (M+H)⁺ for both peaks.

61C. Example 61 and Example 62 were prepared following the proceduresdescribed in step 2G, by replacing 2E/2F with 61B (mixture ofE/Z-isomers); followed by steps 10H; and 1G. The diastereomers were thenseparated by reverse phase chromatography to give Example 61(diastereomer A) and Example 62 (diastereomer B).

Example 61: ¹H NMR (500 MHz, CD₃OD) δ ppm 9.50 (s, 1 H), 7.97 (d, J=2.2Hz, 1 H), 7.68 (dd, J=8.5, 2.2 Hz, 1 H), 7.57-7.60 (m, 2 H), 7.38-7.44(m, 3 H), 7.14 (d, J=15.7 Hz, 1 H), 6.75 (d, J=15.7 Hz, 1 H), 4.95 (dd,J=10.6, 4.5 Hz, 1 H), 3.76 (s, 3 H), 2.47-2.54 (m, 1 H), 2.23-2.33 (m, 2H), 1.91-2.00 (m, 1 H), 1.53-1.61 (m, 1 H), 1.37-1.51 (m, 3 H), 0.86 (d,J=6.3 Hz, 3 H), 0.27-0.36 (m, 1 H). MS (ESI) m/z: 604.3 (M+H)⁺.Analytical HPLC: RT=5.28 min.

Example 62: ¹H NMR (500 MHz, CD₃OD) δ ppm 9.49 (s, 1 H), 7.95 (d, J=2.2Hz, 1 H), 7.66 (dd, J=8.5, 2.2 Hz, 1 H), 7.55-7.60 (m, 2 H), 7.40-7.45(m, 3 H), 7.12 (d, J=15.7 Hz, 1 H), 6.71 (d, J=15.4 Hz, 1 H), 5.00 (dd,J=9.5, 5.4 Hz, 1 H), 3.75 (s, 3 H), 2.41-2.48 (m, 1 H), 2.24-2.32 (m, 1H), 2.11-2.21 (m, 2 H), 1.60-1.69 (m, 1 H), 1.44-1.53 (m, 1 H),1.27-1.42 (m, 2 H), 0.90 (d, J=6.3 Hz, 3 H), 0.68-0.78 (m, 1 H). MS(ESI) m/z: 604.3 (M+H)⁺. Analytical HPLC: RT=5.36 min.

EXAMPLE 63(E)-N-((S)-18-Chloro-11-methyl-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-15-yl)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylamide,1 TFA salt

Example 63 was prepared following the procedure described in 17A, byreplacing 16A with Example 60. ¹H NMR (500 MHz, CD₃OD) δ ppm 0.65-0.76(m, 1 H), 0.99 (d, J=6.3 Hz, 3 H), 1.08-1.18 (m, 1 H), 1.31-1.45 (m, 1H), 1.47-1.61 (m, 1 H), 1.80-1.91 (m, 1 H), 1.93-2.01 (m, 2 H),2.06-2.15 (m, 1 H), 2.35-2.38 (m, 1 H), 4.90 (dd, J=10.2, 4.4 Hz, 1 H),6.79 (d, J=15.7 Hz, 1 H), 7.12 (d, J=15.7 Hz, 1 H), 7.33 (d, J=8.0 Hz, 1H), 7.38-7.44 (m, 1 H), 7.48-7.53 (m, 2 H), 7.57 (d, J=8.5 Hz, 1 H),7.66 (dd, J=8.4, 2.3 Hz, 1 H), 7.99 (d, J=2.5 Hz, 1 H), 9.51 (s, 1 H).MS (ESI) m/z: 565.3(M+H)⁺. Analytical HPLC: RT=7.41 min.

EXAMPLE 64(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((S)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-15-yl)-acrylamide, 1 TFA salt

Example 64 was prepared following the procedures described in step 10D,by replacing 10C with 15B and by replacing but-3-enoic acid withpent-4-enoic acid; followed by steps 2F; 2G, by replacing the hydrogenballoon with hydrogen (50 psi); 10H; and 15D. ¹H NMR (500 MHz, CD₃OD) δppm 0.72-0.82 (m, 1 H), 0.83-0.94 (m, 1 H), 1.42-1.59 (m, 2 H),1.59-1.77 (m, 2 H), 1.98-2.10 (m, 1 H), 2.16-2.25 (m, 1 H), 2.29-2.44(m, 2 H), 5.05 (dd, J=10.0, 4.8 Hz, 1 H), 6.77 (d, J=15.7 Hz, 1 H), 7.11(d, J=15.7 Hz, 1 H), 7.33 (d, J=8.0 Hz, 1 H), 7.40-7.45 (m, 1 H), 7.49(s, 1 H), 7.52-7.58 (m, 3 H), 7.65 (dd, J=8.5, 2.2 Hz, 1 H), 7.95 (d,J=2.2 Hz, 1 H), 9.49 (s, 1 H). MS (ESI) m/z: 517.3(M+H)⁺. AnalyticalHPLC: RT=5.02 min.

EXAMPLE 65(E)-N-((S)-18-Chloro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-15-yl)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylamide,1 TFA salt

Example 65 was prepared following the procedure described in 17A, byreplacing 16A with Example 64. ¹H NMR (500 MHz, CD₃OD) δ ppm 0.75-0.94(m, 1 H), 1.07-1.21 (m, 1 H), 1.33-1.54 (m, 2 H), 1.62-1.72 (m, 2 H),1.86-1.99 (m, 1 H), 2.05-2.16 (m, 1 H), 2.30-2.36 (m, 2 H), 4.90 (dd,J=10.6, 4.5 Hz, 1 H), 6.75 (d, J=15.4 Hz, 1 H), 7.12 (d, J=15.7 Hz, 1H), 7.34 (dd, J=7.8, 1.0 Hz, 1 H), 7.41 (td, J=7.7, 1.4 Hz, 1 H), 7.50(td, J=7.7, 1.6 Hz, 1 H), 7.54 (dd, J=7.7, 1.4 Hz, 1 H), 7.57 (d, J=8.5Hz, 1 H), 7.66 (dd, J=8.5, 2.2 Hz, 1 H), 7.97 (d, J=2.2 Hz, 1 H), 9.50(s, 1 H). MS (ESI) m/z: 551.3(M+H)⁺. Analytical HPLC: RT=6.98 min.

EXAMPLE 66{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8-oxo-9,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

66A. 2-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-5-methoxycarbonylamino-benzoicacid: To a solution of 10B (230 mg, 0.386 mmol) in dry THF(2 ml) at −78°C. under Ar was added methyllithium in THF (0.515 mL, 0.772 mmol). Thereaction was stirred at −78° C. for 30 min after which butyllithium inTHF (0.232 mL, 0.579 mmol) was added dropwise. After 30 min, solid dryice was added to the reaction mixture and the mixture was stirred at−78° C. for 30 min. The reaction mixture was quenched with conc. NH₄Cl(aq). It was extracted with ether and the ether layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated to yield 66A as awhite solid. This was a mixture of product and starting material. Themixture was used in the next step without further purification. MS (ESI)m/z: 561.2 (M+H)⁺.

66B. Example 66 was prepared following the procedures described in step3B, by replacing (1R,4R)-4-((tert-butoxycarbonylamino)methyl)cyclohexanecarboxylic acid with 66A and by replacing 3A withbut-3-en-1-amine; followed by steps 2E/2F; 2G; 10H; and 1G. ¹H NMR (400MHz, CD₃OD) δ ppm 9.51 (s, 1 H), 7.96 (d, J=2.2 Hz, 1 H), 7.63-7.70 (m,2 H), 7.54-7.63 (m, 2 H), 7.51 (s, 1 H), 7.30 (d, J=8.2 Hz, 1 H),7.14-7.24 (d, J=15.7 Hz, 1 H), 6.70-6.81 (d, J=15.7 Hz, 1 H) 4.99-5.13(m, 1 H), 3.68 (s, 3 H), 3.25-3.35 (m, 2 H), 2.24-2.44 (m, 1 H),1.87-2.09 (m, 1 H), 1.42-1.82 (m, 4 H), 0.60-0.89 (m, 1 H), 0.30-0.60(m, 1 H) MS (ESI) m/z: 590.3 (M+H)⁺. Analytical HPLC: RT=4.28 min(Method B).

EXAMPLE 67{(Z)-(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8-oxo-9,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 67 was prepared following the procedures described in step 3B,by replacing(1r,4r)-4-((tert-butoxycarbonylamino)methyl)cyclohexanecarboxylic acidwith 66A and by replacing 3A with but-3-en-1-amine; followed by steps2F; 10H; and 1G. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.52 (s, 1 H), 7.98 (d,J=2.2 Hz, 1 H), 7.53-7.71 (m, 4 H), 7.41 (s, 1 H), 7.35 (d, J=8.8 Hz, 1H), 7.17 (d, J=15.4 Hz, 1 H), 6.79 (d, J=15.4 Hz, 1 H), 5.59-5.73 (m, 1H), 5.29-5.41 (m, 1 H), 5.05-5.14 (m, 1 H), 3.73 (s, 3 H), 3.33-3.46 (m,2 H), 2.72-2.87 (m, 1 H), 2.51-2.65 (m, 1 H), 2.41-2.51 (m, 1 H), 2.34(none, 1 H) MS (ESI) m/z: 588.3 (M+H)⁺. Analytical HPLC: RT=3.60 min(Method B).

EXAMPLE 68{(E)-(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8-oxo-9,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 68 was prepared following the procedures described in step 3B,by replacing(1r,4r)-4-((tert-butoxycarbonylamino)methyl)cyclohexanecarboxylic acidwith 66A and by replacing 3A with but-3-en-1-amine; followed by steps2E; 10H; and 1G. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.51 (s, 1 H), 7.95 (d,J=2.2 Hz, 1 H), 7.65-7.70 (m, 1 H), 7.57 (d, J=8.8 Hz, 2 H), 7.46-7.54(m, 1 H), 7.41 (s, 1 H), 7.24-7.36 (m, 1 H), 7.13-7.17 (m, 1 H),6.71-6.85 (m, 1 H), 5.50-5.62 (m, 1 H), 5.10-5.29 (m, 1 H), 3.69 (s, 3H), 2.95-3.21 (m, 1 H), 2.63-2.87 (m, 1 H), 2.29-2.51 (m, 1 H),2.06-2.29 (m, 1 H). MS (ESI) m/z: 588.3 (M+H)⁺. Analytical HPLC: RT=3.62min. (Method B).

EXAMPLE 69(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((E)-(S)-9-oxo-8,10,17,19-tetraaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-acrylamide,1 TFA salt

69A.{(S)-1-[4-[2-(3-Allyl-ureido)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-but-3-enyl}-carbamicacid tert-butyl ester: To a cooled (0° C.), orange solution of 15B (150mg, 0.327 mmol) and pyridine (26.5 μL, 0.327 mmol) in DCM (1308 μL) wasadded dropwise allyl isocyanate (28.9 μL, 0.327 mmol). After 35 min,additional allyl isocyanate (28.9 μL, 0.327 mmol) was added. After anadditional 30 min, sat. NaHCO₃(aq) (1.31 mL) was added and the reactionwas stirred vigorously. The reaction was allowed to warm to rt and stirovernight. The reaction was partitioned between 1:1 mixture of DCM andsat. NaHCO₃(aq) and the layers were separated. The aqueous layer wasextracted with DCM (2×). The organic layers were combined, washed withbrine, dried over MgSO₄, filtered and concentrated to give an orangeresidue. Purification by normal phase chromatography gave 69A (109.8 mg,59.5% yield) as a yellow foam. MS (ESI) m/z: 542.5(M+H)⁺.

69B. Example 69 was prepared following the procedures described in step2E, by replacing 2D with 69A; followed by steps 10H; and 15D. ¹H NMR(500 MHz, CD₃OD) δ ppm 2.52-2.70 (m, 1 H), 2.81-2.93 (m, 1 H), 3.48-3.59(m, 2 H), 5.15 (dd, J=10.0, 5.4 Hz, 1 H), 5.56-5.73 (m, 2 H), 6.77 (d,J=15.4 Hz, 1 H), 7.15 (d, J=15.4 Hz, 1 H), 7.28 (d, J=8.0 Hz, 1 H), 7.33(td, J=7.6, 1.1 Hz, 1 H), 7.39 (s, 1 H), 7.46-7.50 (m, 2 H), 7.58 (d,J=8.5 Hz, 1 H), 7.68 (dd, J=8.5, 2.2 Hz, 1 H), 7.98 (d, J=2.2 Hz, 1 H),9.51 (s, 1 H). MS (ESI) m/z: 516.2(M+H)⁺. Analytical HPLC: RT=4.77 min.

EXAMPLE 70{(E)-(S)-15-[(E)-3-(2-Acetyl-5-chloro-phenyl)-acryloylamino]-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 70 was prepared following the procedures described in step 1 OH,by replacing 10G with 39A; followed by step 15D, by replacingIntermediate 2 with Intermediate 4 and by replacing Hunig's base withtriethylamine. ¹H NMR (500 MHz, CD₃OD) δ ppm 7.98 (d, J=15.9 Hz, 1 H),7.91 (d, J=8.2 Hz, 1 H), 7.66 (d, J=2.2 Hz, 1 H), 7.59 (s, 1 H), 7.54(dd, J=8.8, 2.2 Hz, 1 H), 7.41-7.43 (m, 3 H), 6.55 (d, J=15.9 Hz, 1 H),5.54-5.62 (m, 1 H), 5.38-5.46 (m, 1 H), 5.13 (dd, J=9.9, 4.4 Hz, 1 H),3.75 (s, 3 H), 2.79-2.87 (m, 1 H), 2.34-2.63 (m, 8 H). MS (ESI) m/z:562.5 (M+H)⁺. Analytical HPLC: RT=5.36 min.

EXAMPLE 71(E)-N-((E)-(S)-18-Chloro-9-oxo-8,10,17,19-tetraaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylamide,1 TFA salt

Example 71 was prepared following the procedure described in 17A, byreplacing 16A with Example 69. ¹H NMR (500 MHz, CD₃OD) δ ppm 2.40-2.57(m, 1 H), 2.72-2.84 (m, 1 H), 3.45-3.68 (m, 2 H), 5.03 (dd, J=9.9, 4.9Hz, 1 H), 5.37-5.53 (m, 1 H), 5.54-5.67 (m, 1 H), 6.78 (d, J=15.4 Hz, 1H), 7.15 (d, J=15.4 Hz, 1 H), 7.28-7.34 (m, 2 H), 7.43-7.48 (m, 2 H),7.58 (d, J=8.8 Hz, 1 H), 7.67 (dd, J=8.8, 2.2 Hz, 1 H), 7.97-8.00 (m,1H), 9.52 (s, 1H). MS (ESI) m/z: 550.2 (M+H)⁺. Analytical HPLC: RT=6.48min.

EXAMPLE 72{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-12-methyl-3-oxo-12,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamic acid methyl ester, 1 TFA salt

72A.(S)-3-[4-(2-Allyl-4-methoxycarbonylamino-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-3-tert-butoxycarbonylamino-propionicacid benzyl ester: 23A (0.30 g, 0.426 mmol), allyltributylstannane(0.282 g, 0.853 mmol), CsF (0.162 g, 1.065 mmol), Pd₂dba₃ (0.020 g,0.021 mmol), and tri-(tert-butyl)phosphine (0.173 g, 0.085 mmol) wereadded together with dioxane (10 mL). The mixture was heated to 90° C.under argon. After 2.5 h, an additional two equivalents ofallyltributylstannane and CsF, and a catalytic amount of Pd₂dba₃ andtri-(tert-butyl)phosphine were added. The mixture was stirred at 90° C.under argon for 3 h. The solvent was removed and the residue waspartitioned between EtOAc and water. The EtOAc solution was washed withbrine, dried over Na₂SO₄ and concentrated. The crude product waspurified by normal phase chromatography to give 72A (0.26 g, 92% yield).MS (ESI) m/z: 665.3 (M+H)⁺.

72B.(S)-3-(4-(2-Allyl-4-(methoxycarbonylamino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-3-(tert-butoxycarbonylamino)propanoicacid: 72A (0.26 g, 0.39 mmol) was dissolved in THF (6 mL) and 2N LiOH (2mL) was added. The mixture was stirred at rt under argon for 20 h. Thesolvent was removed and the residue was diluted with water and acidifiedto pH about 5 with 1N HCl. The mixture was extracted with EtOAc. Thecombined EtOAc solution was washed with brine, dried over Na₂SO₄ andconcentrated to give 72B (0.24 g, 100% yield). MS (ESI) m/z: 575.3(M+H)⁺.

72C.{3-Allyl-4-[2-[(S)-2-(allyl-methyl-carbamoyl)-1-tert-butoxycarbonylamino-ethyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: To a solution of 72B in DMF (4 mL) were added PyBOP(0.26 g, 0.47 mmol), Et₃N (0.22 mL, 1.56 mmol), and methylallylamine(0.71 g, 0.998 mmol). The mixture was stirred at rt under argon for 1.5h. Water was added and the mixture was extracted with EtOAc. Thecombined EtOAc solution was washed with brine, dried over Na₂SO₄ andconcentrated. The crude product was purified by normal phasechromatography to give 72C (0.16 g, 64% yield). MS (ESI) m/z: 628.4(M+H)⁺.

72D. Example 72 was prepared following the procedures described in step2E/2F, by replacing 2D with 72C; followed by steps 2G; 1F, by replacingethanol with methanol; and 1G. ¹H NMR (400 MHz, CD₃OD, rotamers) δ ppm9.52 (s, 1H), 9.30 (s, 1H), 8.00 (dd, J=14.56 and 2.26 Hz, 1H),7.64-7.77 (m, 1 H), 7.55-7.63 (m, 1 H), 7.46 (dd, J=10.42 and 2.13 Hz,1H), 7.36-7.43 (m, 1 H), 7.35 (d, J=1.25 Hz, 1H), 7.30 (d, J=8.03 Hz,1H), 7.21 (dd, J=15.69 and 5.14 Hz, 1H), 5.67 (m, 1H), 5.53 (m, 1H),4.46 (m, 1H), 3.75 (two singlets, 3H), 3.47 (m, 1H), 3.28 (m, 2H), 3.25(m, 1H), 2.92 (two singlets, 3H), 2.68 (m, 2H), 2.29 (m, 1H), 1.29 (m,1H). LC-MS (ESI) m/z: 604.3 (M+H)⁺. Analytical HPLC: RT=6.22/6.49 min(two rotational isomers).

EXAMPLE 73{(E)-(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-10,10-difluoro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 73 was prepared following the procedures described in step 10D,by replacing but-3-enoic acid with 2,2-difluoropent-4-enoic acid;followed by steps 2E; 10H; and 1G. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.52(s, 1 H), 7.97 (s, 1 H), 7.67 (s, 1 H), 7.54-7.62 (m, 2 H), 7.49 (s, 1H), 7.38-7.47 (m, 2 H), 7.12-7.16 (d, J=15.4 Hz, 1 H), 6.74-6.78 (d,J=15.4 Hz, 1 H), 5.69-5.81 (m, 1 H), 5.23-5.35 (m, 1 H), 5.06-5.14 (m, 1H), 3.76 (s, 3 H), 2.75-3.00 (m, 3 H), 2.53-2.68 (m, 1 H) MS (ESI) m/z:624.3 (M+H)⁺. Analytical HPLC: RT=4.31 min. (Method B).

EXAMPLE 74{(Z)-(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-10,10-difluoro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 74 was prepared following the procedures described in step 10D,by replacing but-3-enoic acid with 2,2-difluoropent-4-enoic acid;followed by steps 2F; 10H; and 1G. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.51(s, 1 H), 7.98 (s, 1 H), 7.52-7.76 (m, 3 H), 7.27-7.52 (m, 3 H),7.04-7.27 (m, 1 H), 6.66-6.87 (m, 1 H), 5.50-5.75 (m, 2 H), 5.09-5.29(m, 1 H), 3.76 (s, 3 H), 2.52-3.18 (m, 4 H). MS (ESI) m/z: 624.2 (M+H)⁺.Analytical HPLC: RT=4.24 min. (Method B).

EXAMPLE 75{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acroyolamino]-8-oxa-13,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

75A. (S)-2-Benzyloxycarbonylamino-3-tert-butoxycarbonylamino-propionicacid 2-(2-hydroxy-4-methoxycarbonylamino-phenyl)-2-oxo-ethyl ester: Thiscompound was prepared following the procedures described in 2A, byreplacing (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with(S)-2-Benzyloxycarbonylamino-3-tert-butoxycarbonylamino-propionic acidand by replacing 2-bromo-1-(2-bromophenyl)ethanone with methyl4-(2-bromoacetyl)-3-hydroxyphenylcarbamate. MS (ESI) m/z: 546.3 (M+H)⁺.

75B. (S)-2-Benzyloxycarbonylamino-3-tert-butoxycarbonylamino-propionicacid 2-(2-allyloxy-4-methoxycarbonylamino-phenyl)-2-oxo-ethyl ester: Toa solution of 75A (3.3 g, 6.05 mmol) in DMF (8.5 mL) was added potassiumcarbonate (1.254 g, 9.07 mmol), followed by addition of3-bromoprop-1-ene (0.580 mL, 6.65 mmol). The reaction was heated at 70°C. for 2 hr. The reaction mixture turned dark red. It was cooled down,partitioned between water and EtOAc. The organic layer was washed withwater, brine, dried over MgSO₄, filtered off solid and concentrated.Purification by normal phase chromatography gave 75B as a pale yellowfoam (2.05 g, 58%). MS (ESI) m/z: 586.4 (M+H)⁺.

75C.{4-[2-((S)-2-Allylamino-1-benzyloxycarbonylamino-ethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-allyloxy-phenyl}-carbamicacid methyl ester: This compound was prepared following the proceduresdescribed in step 2B, by replacing 2A with 75B; followed by steps 3C;and 75B. MS (ESI) m/z: 636.5 (M+H)⁺.

75D. Example 75 was prepared following the procedures described in step20D, by replacing 20C with 75C; followed by steps 2E/2F; 2G; 1G; and10H. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.54 (s, 1 H), 7.98 (d, J=2.2 Hz, 1H), 7.68 (dd, J=8.5, 2.5 Hz, 1 H), 7.60 (d, J=8.3 Hz, 1 H), 7.45 (d,J=8.2 Hz, 1 H), 7.40 (s, 1 H), 7.34 (s, 1 H), 7.23 (d, J=15.9 Hz, 1 H),6.98-7.02 (m, 1 H), 6.68 (d, J=15.9 Hz, 1 H), 5.42 (dd, J=7.1, 3.3 Hz, 1H), 4.14 (s, 2 H), 3.75 (s, 3 H), 3.51-3.59 (m, 1 H), 3.42-3.49 (m, 1H), 3.10-3.22 (m, 2 H), 1.95-2.09 (m, 4 H). MS (ESI) m/z: 578.3 (M+H)⁺.Analytical HPLC: RT=3.63 min. (Method B).

EXAMPLE 76{(E)-(S)-15-[(E)-3-(2-Acetyl-5-chloro-phenyl)-acryloylamino]-18-chloro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

76A.[(E)-(S)-18-Chloro-5-methoxycarbonylamino-9-oxo-17-(2-trimethylsilanylethoxymethyl)-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl]-carbamicacid tert-butyl ester: To a solution of 39A (0.37 g, 0.632 mmol) inacetonitrile (3 mL)/chloroform (3 mL) was added NCS (0.101 g, 0.758mmol). The reaction was heated at 65° C. for 3 h, cooled to rt andconcentrated. Purification by reverse phase chromatography gave 76A(0.205 g, 0.331 mmol, 52.3%) as a white solid. MS (ESI) m/z: 620.1(M+H)⁺.

76B.((E)-(S)-15-Amino-18-chloro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl)-carbamicacid methyl ester, 2 HCl salt: The mixture of 76A (0.205 g, 0.279 mmol)and 4M HCl in dioxane (2 mL, 8.00 mmol) in a sealed tube was heated at75° C. After 2h, the reaction was cooled to rt. The solid was collectedby filtration, rinsed with hexane, and then dried to afford 76B (0.12 g,93%) as a white solid. MS (ESI) m/z: 390.1 (M+H)⁺.

76C. Example 76 was prepared following the procedure described in step15D, by replacing 15C with 76B, by replacing Intermediate 2 withIntermediate 4 and by replacing Hunig's base with triethylamine. ¹H NMR(500 MHz, CD₃OD) δ ppm 7.97 (d, J=15.4 Hz, 1 H), 7.89 (d, J=8.2 Hz, 1H), 7.67 (d, J=2.2 Hz, 1 H), 7.59 (s, 1 H), 7.52 (dd, J=8.2, 2.2 Hz, 1H), 7.41 (s, 2 H), 6.55 (d, J=15.9 Hz, 1 H), 5.52-5.60 (m, 1 H),5.34-5.42 (m, 1 H), 5.02 (dd, J=10.4, 4.4 Hz, 1 H), 3.75 (s, 3 H),2.72-2.79 (m, 1 H), 2.59 (s, 3 H), 2.32-2.53 (m, 5 H). MS (ESI) m/z:596.0 (M+H)⁺. Analytical HPLC: RT=6.86 min.

EXAMPLE 77{(E)-(S)-18-Chloro-15-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 77 was prepared following the procedure described in 1G, byreplacing 1F with 76B. ¹H NMR (400 MHz, DMSO-d₆+2 drops D₂O) δ ppm 9.76(s, 1 H), 7.92 (d, J=2.2 Hz, 1 H), 7.68 (dd, J=8.2, 2.2 Hz, 1 H), 7.64(d, J=8.2 Hz, 1 H), 7.38 (s, 1 H), 7.31 (dd, J=8.8, 2.2 Hz, 1 H), 7.26(d, J=8.3 Hz, 1 H), 6.77-6.87 (m, 2 H), 5.37-5.47 (m, 1 H), 5.12-5.21(m, 1 H), 4.87 (dd, J=10.2, 4.1 Hz, 1 H), 3.61 (s, 3 H), 2.12-2.33 (m, 6H). MS (ESI) m/z: 622.0 (M+H)⁺. Analytical HPLC: RT=6.46 min.

EXAMPLE 78{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-10,10-difluoro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester 1 TFA salt

Example 78 was prepared following the procedures described in step 10D,by replacing but-3-enoic acid with 2,2-difluoropent-4-enoic acid;followed by steps 2E/2F; 2G; 10H; and 1G. ¹H NMR (400 MHz, CD₃OD) δ ppm9.50 (s, 1 H), 7.96 (d, J=2.2 Hz, 1 H), 7.67 (d, J=2.2 Hz, 1 H), 7.65(d, J=2.2 Hz, 1 H), 7.61 (s, 1 H), 7.57 (d, J=8.8 Hz, 1 H), 7.51 (s, 1H), 7.47-7.50 (m, 1 H), 7.11 (d, J=15.9 Hz, 1 H), 6.75 (d, J=15.4 Hz, 1H), 5.53-5.65 (m, 1 H), 3.76 (s, 3 H), 1.95-2.29 (m, 4 H), 1.56 (d,J=4.9 Hz, 2 H), 0.68-0.94 (m, 2 H). MS (ESI) m/z: 626.3 (M+H)⁺.Analytical HPLC: RT=4.27 min. (Method B).

EXAMPLE 79{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-13-oxo-8,12,17,19-tetraaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

79A. (S)-Benzyl3-(4-(2-(3-(benzyloxycarbonylamino)propylamino)-4-(methoxycarbonylamino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-3-(tert-butoxycarbonylamino)propanoate:To a solution of 23A (200 mg, 0.284 mmol) in DMSO were added benzyl3-aminopropylcarbamate, HCl salt (83 mg, 0.341 mmol), L-proline (6.54mg, 0.057 mmol), CuI (5.41 mg, 0.028 mmol) and K₂CO₃ (118 mg, 0.853mmol). The reaction was purged with argon for 3 min. The reaction wasstirred at 80° C. for 16 h. The reaction was cooled to rt and then wasdiluted with EtOAc, washed with H₂O, saturated NaHCO₃ and brine. Theorganic phase was dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by normal phase chromatography to give 79A (47 mg,20% yield) as a light tan solid. LC-MS (ESI) m/z: 831.4 (M+H)⁺.

79B. Example 79 was prepared following the procedures described in step2G, by replacing 2E with 79A; followed by steps 23E; 1F, by replacingethanol with methanol; and 1G. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.52 (1 H,s), 7.99 (1 H, d, J=2.26 Hz), 7.83 (1 H, s), 7.64-7.71 (2 H, m),7.55-7.62 (2 H, m), 7.25 (1 H, dd, J=8.53, 2.01 Hz), 7.21 (1 H, d,J=15.56 Hz), 6.74 (1 H, d, J=15.56 Hz), 5.60 (1 H, dd, J=9.29, 4.27 Hz),3.77 (3 H, s), 3.61-3.71 (1 H, m), 3.43-3.51 (1 H, m), 3.34-3.40 (2 H,m), 2.85-2.94 (1 H, m), 2.75-2.84 (1 H, m), 2.13-2.27 (2 H, m). LC-MS(ESI) m/z: 591.2 (M+H)⁺. Analytical HPLC: RT=4.836 min.

EXAMPLE 80{(E)-(S)-15-[(4-Aminomethyl-cyclohexanecarbonyl)-amino]-18-chloro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

Example 80 was prepared following the procedures described in step 3B,by replacing 3A with 76B and by running the reaction at 55° C.; followedby step 3C. ¹H NMR (500 MHz, CD₃OD) δ ppm 7.53 (d, J=1.4 Hz, 1 H), 7.42(dd, J=8.5, 2.2 Hz, 1 H), 7.36 (d, J=8.5 Hz, 1 H), 5.46-5.54 (m, 1 H),5.27-5.36 (m, 1 H), 4.79-4.90 (m, 1 H), 3.75 (s, 3 H), 2.79 (d, J=6.9Hz, 2 H), 2.58-2.66 (m, 1 H), 2.26-2.48 (m, 6 H), 1.85-1.98 (m, 4 H),1.57-1.67 (m, 1 H), 1.42-1.55 (m, 2 H), 1.03-1.16 (m, 2 H). MS (ESI)m/z: 529.1 (M+H)⁺. Analytical HPLC: RT=3.31 min.

EXAMPLE 82[(E)-(S)-18-Chloro-15-(2,6-difluoro-4-methyl-benzoylamino)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]-carbamicacid methyl ester, 1 TFA salt

Example 82 was prepared following the procedure described in step 15D,by replacing 15C with 76B, by replacing Intermediate 2 with2,6-difluoro-4-methyl benzoic acid, by replacing Hunig's base withtriethylamine and running the reaction at 55° C. ¹H NMR (500 MHz,DMSO-d₆+2 drops D₂O) δ ppm 7.39 (d, J=1.6 Hz, 1 H), 7.33 (dd, J=8.8, 2.2Hz, 1 H), 7.29 (d, J=8.3 Hz, 1 H), 6.93 (d, J=8.8 Hz, 2 H), 5.40-5.48(m, 1 H), 5.17-5.24 (m, 1 H), 5.06 (dd, J=9.1, 4.1 Hz, 1 H), 3.62 (s, 3H), 2.37-2.43 (m, 1 H), 2.24-2.36 (m, 6 H), 2.15-2.22 (m, 2 H). MS (ESI)m/z: 544.2 (M+H)⁺. Analytical HPLC: RT=6.67 min.

EXAMPLE 83{(E)-(S)-18-Chloro-15-[(4-methyl-cyclohexanecarbonyl)-amino]-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 83 was prepared following the procedure described in step 15D,by replacing 15C with 76B, by replacing Intermediate 2 with4-methylcyclohexanecarboxylic acid, by replacing Hunig's base withtriethylamine and running the reaction at 55° C. ¹H NMR (500 MHz,DMSO-d₆+2 drops D₂O) δ ppm 7.40 (d, J=2.2 Hz, 1 H), 7.32 (dd, J=8.8, 2.2Hz, 1 H), 7.27 (d, J=8.8 Hz, 1 H), 5.37-5.45 (m, 1 H), 5.13-5.21 (m, 1H), 4.81 (dd, J=9.6, 4.1 Hz, 1 H), 3.62 (s, 3 H), 2.14-2.38 (m, 6 H),2.03-2.11 (m, 1 H), 1.56-1.70 (m, 4 H), 1.16-1.32 (m, 3 H), 0.75-0.89(m, 5 H). MS (ESI) m/z: 514.2 (M+H)⁺. Analytical HPLC: RT=6.84 min.

EXAMPLE 84{(E)-(S)-15-[(1-Amino-5,6,7,8-tetrahydro-isoquinoline-6-carbonyl)-amino]-18-chloro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 2 TFA salt (mixture of diastereomers)

Example 84 was prepared following the procedure described in 15D, byreplacing 15C with 76B, by replacing Intermediate 2 with Intermediate 5,by replacing Hunig's base with triethylamine and running the reaction at55° C. ¹H NMR (500 MHz, DMSO-d₆+2 drops D₂O) δ ppm 7.65-7.70 (m, 1 H),7.42 (s, 1 H), 7.35-7.39 (m, 1 H), 7.28-7.33 (m, 1 H), 6.69-6.74 (m, 1H), 5.42-5.51 (m, 1 H), 5.16-5.26 (m, 1 H), 4.86-4.92 (m, 1 H), 3.65 (s,3 H), 2.77-2.85 (m, 2 H), 2.63-2.72 (m, 1 H), 2.45-2.53 (m, 1 H),2.18-2.44 (m, 7 H), 2.00-2.09 (m, 1 H), 1.63-1.78 (m, 1 H). MS (ESI)m/z: 564.2 (M+H)⁺. Analytical HPLC: RT=3.56 min.

EXAMPLE 85[(E)-(S)-15-(4-Aminomethyl-benzoylamino)-18-chloro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]-carbamicacid methyl ester, 2 TFA salt

85A.{(E)-(S)-15-[4-(tert-Butoxycarbonylamino-methyl)-benzoylamino]-18-chloro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt: This compound was prepared following theprocedure described in 15D, by replacing 15C with 76B, by replacingIntermediate 2 with 4-((tert-butoxycarbonylamino)methyl)benzoic acid, byreplacing Hunig's base with triethylamine and running the reaction at55° C. MS (ESI) m/z: 623.3 (M+H)⁺.

85B. Example 85 was prepared following the procedure described in 3C, byreplacing 3B with 85A. ¹H NMR (500 MHz, DMSO-d₆+2 drops D₂O) δ ppm 7.93(d, J=8.5 Hz, 2 H), 7.54 (d, J=8.3 Hz, 2 H), 7.46 (s, 1 H), 7.39 (dd,J=8.5, 2.2 Hz, 1 H), 7.32 (d, J=8.5 Hz, 1 H), 5.52-5.60 (m, 1 H),5.24-5.32 (m, 1 H), 5.15 (dd, J=9.4, 4.7 Hz, 1 H), 4.09 (s, 2 H), 3.68(s, 3 H), 2.23-2.54 (m, 6 H). MS (ESI) m/z: 523.1 (M+H)⁺. AnalyticalHPLC: RT=3.44 min.

EXAMPLE 87(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((E)-(S)-9-oxo-10-oxa-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-acrylamide,1 TFA salt

Example 87 was prepared following the procedures described in step 69A,by replacing allyl isocyanate with allyl chloroformate; followed bysteps 2E; 10H; and 15D. ¹H NMR (500 MHz, CD₃OD) δ ppm 2.53-2.69 (m, 1H), 2.88-2.98 (m, 1 H), 4.28-4.43 (m, 2 H), 5.16 (dd, J=10.5, 5.2 Hz, 1H), 5.63-5.79 (m, 1 H), 5.84-5.94 (m, 1 H), 6.78 (d, J=15.7 Hz, 1 H),7.14 (d, J=15.7 Hz, 1 H), 7.25 (d, J=7.7 Hz, 1 H), 7.39 (t, J=7.4 Hz, 1H), 7.44 (s, 1 H), 7.48-7.54 (m, 2 H), 7.58 (d, J=8.5 Hz, 1 H), 7.68(dd, J=8.5, 2.2 Hz, 1 H), 7.98 (d, J=2.2 Hz, 1 H), 9.51 (s, 1 H). MS(ESI) m/z: 517.2(M+H)⁺. Analytical HPLC: RT=5.12 min.

EXAMPLE 88{(E)-(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,17-diaza-tricyclo[14.3.1.0^(2,7)]icosa-1(20),2(7),3,5,12,16,18-heptaen-5-yl}-carbamic acid methyl ester, 1 TFAsalt

88A.(S,E)-N-((4-Chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide:Reference: Liu, G. et al., J Org. Chem., 64:1278 (1999). To a solutionof S-(−)-t-butyl-sulfinamide (0.856 g, 7.06 mmol) in dichloromethane(14.13 mL) was added sequentially copper(II) sulfate (2.481 g, 15.54mmol) and 4-chloropicolinaldehyde [1.0 g, 7.06 mmol, prepared accordingto a modified described by Negi (Synthesis, 991 (1996))]. The whitesuspension was stirred at rt. After 3h, the brown suspension wasfiltered through CELITE®, eluting with DCM, to give a clear brownfiltrate. Concentration gave a brown oil weighing 1.85 g. Purificationby normal phase chromatography gave 1.31 g of 88A as a clear, yellowoil. MS (ESI) m/z: 245.0 (M+H)⁺.

88B.(S)-N-((S)-1-(4-Chloropyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfinamide:Using a modified procedure described by Kuduk (Tetrahedron Letters,45:6641 (2004)). To a cooled (−78° C.), clear, yellow solution of 88A(2.50 g, 10.21 mmol) in THF (34.0 mL) was added dropwise allylmagnesiumbromide (1.0 M in diethyl ether, 14.30 mL, 14.30 mmol) over 25 min. Theresulting orange-brown suspension was stirred at −78° C. After 30 min,additional allylmagnesium bromide (1.40 mL) was added. After 1h, thereaction was stopped by quenching with sat. NH₄Cl. The resultingorange-brown suspension was allowed to warm to rt. The reaction waspartitioned between water and EtOAc and the layers were separated. Theaqueous layer was extracted with EtOAc (1×). The combined organic layerswere washed with sat. NaHCO₃, brine, dried over Na₂SO₄, filtered andconcentrated to give a blue oil weighing 3.22 g. Purification by normalphase chromatography gave 2.55 g (87%) of 88B as an orange-brown solid.The diastereomeric excess based on HPLC of the reaction mixture was1:5.7 diastereomer A:diastereomer B. MS (ESI) m/z: 287.1 (M+H)⁺.

88C.(S)-N-((S)-1-(4-(2-Amino-4-nitrophenyl)pyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfinamide:To a RBF was added 88B (1.40 g, 4.88 mmol), Intermediate 12 (2.441 g,9.76 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (0.399 g, 0.488 mmol), andpotassium phosphate, tribasic (2.072 g, 9.76 mmol). The RBF was equippedwith a reflux condensor then the apparatus was purged with argon forseveral minutes. Next, degassed DMSO (24.41 mL) was added followed bydegassed water (0.440 mL, 24.41 mmol). The bright orange suspension waswarmed to 90° C. After 5 h, the reaction was stopped and cooled to rt.The black mixture was filtered to remove the solid, rinsing with EtOAc.The filtrate was then partitioned between EtOAc and water and the layerswere separated. The aqueous layer was extracted with EtOAc (1×). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated to give a thick black oil weighing3.8 g. Purification by normal phase chromatography gave 1.70 g as amixture of diastereomers. The diastereomers were separated by reversephase chromatography. Pure fractions of diastereomer A were neutralizedand worked up as described in 2D to give 0.139 g of diastereomer A as anorange foam. Pure fractions of diastereomer B were neutralized andworked up as described in 2D to give 0.996 g of 88C, as an orange foam.Diastereomer B: MS (ESI) m/z: 389.2 (M+H)⁺.

88D.{(S)-1-[4-(2-Amino-4-nitro-phenyl)-pyridin-2-yl]-but-3-enyl}-carbamicacid tert-butyl ester: To a clear, orange solution of 88C (1.22 g, 3.14mmol) in methanol (31.4 mL) was added 4 M HCl in dioxane (15.70 mL, 62.8mmol). The reaction was slightly exothermic to the touch, so a waterbath was used. After 1 h, the orange solution was concentrated to givean orange residue. The residue was suspended in DCM and concentrated.The residue was again suspended in DCM and then concentrated to give theamine as an orange solid. MS (ESI) m/z: 285.2 (M+H)⁺. The orange solidwas suspended in DCM (10.46 mL) and then BOC₂O (0.802 mL, 3.45 mmol) wasadded. Next, triethylamine (1.750 mL, 12.56 mmol) was added and thereaction became an orange-brown suspension. The reaction was stirred atrt. After 2 h, the reaction was diluted with EtOAc and washed with sat.NaHCO₃. The aqueous layer was extracted with EtOAc (1×). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered, and concentrated to give a dark brown foam weighing 1.53 g.Purification by normal phase chromatography gave 1.15 g (95%) of 88D asa yellow foam. MS (ESI) m/z: (M+H)⁺.

88E.{(S)-1-[4-(4-Nitro-2-pent-4-enoylamino-phenyl)-pyridin-2-yl]-but-3-enyl}-carbamicacid tert-butyl ester: To a cooled (−5° C.) clear, yellow solution of88D (0.413 g, 1.074 mmol) and pent-4-enoic acid (0.220 mL, 2.149 mmol)in ethyl acetate (10.74 mL) was added Hunig's Base (0.563 mL, 3.22 mmol)and propane phosphonic acid anhydride (1.266 mL, 2.149 mmol). Followingthe addition, the reaction was allowed to warm to rt and stir overnight.After 17.5 h, additional pent-4-enoic acid (2×0.220 mL, 2.149 mmol),Hunig's Base (2×0.563 mL, 3.22 mmol) and propane phosphonic acidanhydride (2×1.266 mL, 2.149 mmol) were added. After an additional 24 h,the reaction was stopped, partitioned between EtOAc and sat. NaHCO₃, andthe layers were separated. The aqueous layer was extracted with EtOAc(1×). The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated to give an orange oil weighing0.739 g. Purification by normal phase chromatography gave 0.448 g (88%)of 88E as a pale, yellow foam. MS (ESI) m/z: 467.3 (M+H)⁺.

88F.{4-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-pyridin-4-yl]-3-pent-4-enoylamino-phenyl}-carbamicacid methyl ester: To a clear, yellow solution of 88E (0.330 g, 0.707mmol) in MeOH (14.15 mL) was added zinc dust (0.463 g, 7.07 mmol) andammonium chloride (0.378 g, 7.07 mmol). The gray suspension was stirredvigorously at rt. After 2 h, the reaction was stopped and then filteredthrough a 0.45 micron nylon filter, eluting with methanol. The filtratewas concentrated to give a clear, pale yellow residue. The residue waspartitioned between EtOAc and 0.25 M HCl (20 mL) and the layers wereseparated. The organic layer was extracted with 0.25 M HCl (2×10 mL).The acid layer was basified with 1.5 M K₂HPO₄ and then extracted withEtOAc (3×). The combined organic layers were washed with brine, driedover sodium sulfate, filtered and concentrated to give the aniline as apale, yellow foam weighing 0.3047 g. MS (ESI) m/z: 437.3 (M+H)⁺. To acooled (−5° C.) clear, pale yellow solution of the aniline (0.3047 g,0.698 mmol) in dichloromethane (6.98 mL) was added pyridine (0.056 mL,0.698 mmol) and methyl chloroformate (0.054 mL, 0.698 mmol). Theresulting bright yellow solution was stirred at −5° C. for 1h. Thereaction was diluted with EtOAc and washed with sat. NaHCO₃. The aqueouslayer was extracted with EtOAc (2×). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentratedto give a white foam weighing 0.345 g. Purification by normal phasechromatography gave 0.312 g (90%) of 88F, as a white foam. MS (ESI) m/z:495.3 (M+H)⁺.

88G.((E)-(S)-15-tert-Butoxycarbonylamino-9-oxo-8,17-diaza-tricyclo[14.3.1.0^(2,7)]icosa-1(20),2(7),3,5,12,16,18-heptaen-5-yl)-carbamic acid methyl ester, 1 TFAsalt: To a flame-dried 500 mL RBF was added 88F (0.116 g, 0.235 mmol),pTsOH monohydrate (0.049 g, 0.258 mmol), and DCM (235 mL). The flask wasequipped with a reflux condensor and the clear, colorless solution wasdegassed with argon for 30 min. The reaction was then warmed to 40° C.for 1 h. In a separate, flame-dried RBF was added Grubbs (II) (0.020 g,0.023 mmol) and the flask was purged with argon for several minutes.Degassed DCM (2 mL) was added to give a clear, burgundy solution. Thesolution of Grubbs (II) was added dropwise over 5 min to the abovereaction. The resulting clear yellow solution was stirred at 40° C. Thereaction was stopped after a total of 1.5 h. Upon cooling to rt, thereaction was washed with sat. NaHCO₃, brine, dried over sodium sulfate,filtered, and concentrated to give dark brown solid weighing 0.134 g.Purification by reverse phase chromatography gave 0.102 g (75%) of 88 G,as an off-white solid. MS (ESI) m/z: 467.3 (M+H)⁺.

88H. Example 88 was prepared following the procedures described in step3C, by replacing 3B with 88G; followed by step 1G. ¹H NMR (500 MHz,DMSO-d₆ and D₂O) δ ppm 9.89 (s, 1 H), 9.81 (s, 1 H), 8.63 (d, J=5.5 Hz,1 H), 7.95 (d, J=2.2 Hz, 1 H), 7.73 (dd, J=8.8, 2.2 Hz, 1 H), 7.69 (d,J=8.2 Hz, 1 H), 7.38-7.48 (m, 3 H), 7.31 (d, J=8.2 Hz, 1 H), 7.18 (s, 1H), 6.98 (d, J=15.4 Hz, 1 H), 6.80 (d, J=15.4 Hz, 1 H), 5.37-5.48 (m, 1H), 5.18-5.28 (m, 1 H), 4.93 (dd, J=9.1, 3.6 Hz, 1 H), 3.67 (s, 3 H),2.50-2.55 (m, 1 H), 2.17-2.37 (m, 5 H). MS (ESI) m/z: 599.3 (M+H)⁺.Analytical HPLC (Method D): RT=4.57 min.

EXAMPLE 89 Methyl((E)-3-chloro-5-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamido)-11-oxo-5,6,9,10,11,12-hexahydrobenzo[b]pyridazino[3,4-d][1]azacyclododecin-14-yl)carbamate

89A. tert-Butyl 1-3,6-dichloropyridazin-4-yi)but-3-enylcarbamate: To acooled (−78° C.) solution of tert-batyl(3,6-dichloropyridazin-4-yl)methylearbamate (3.28 g, 11.79 mmol)prepared by following a literature procedure (Cowden. C. J., Org. Lett.,4497-4499 (2003)) in THF (15 mL) was added TMEDA (1.780 mL, 11.79 mmol).Then sec-butyllithium (1.4M in cyclohexane, 21.06 mL, 29.5 mmol) wasadded dropwise at −78° C. The reaction was warmed to −40° C. over 30 minbefore it was cooled to −78° C. Allyl bromide (1.496 mL, 17.69 mmol) wasadded at −78° C. The reaction was stirred under argon at −78° C. for 30min and then was quenched with NH₄Cl solution. The reaction mixture wasdiluted with EtOAc, washed with 1M HCl, saturated NaHCO₃ and brine. Theorganic phase was dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by normal phase chromatography to give 89A (1.49 g,40% yield) as a solid. LC-MS (ESI) m/z: 318.1 (M+H)⁺.

89B. tert-Butyl(1-(3-(2-amino4-nitrophenyl)-6-chloropyridazin-4-yl)but-3-en-1-y1)carbarnate:A flask containing 89A (1.49 g, 4.68 mmol),2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-nitroaniline (1.756 g, 7.02mmol) and Cs₂CO₃ (3.81 g, 11.71 mmol) was purged with argon. To it wereadded dioxane (40 mL), tri-tert-butylphosphine tetrafluoroborate (0.204g, 0.702 mmol) and Pd₂dba₃ (0.429 g, 0.468 mmol) at rt. The reaction wasstirred under argon at 90° C. for 3 h. The reaction was cooled to rt.The solid was filtered off and the solvent was removed to give a darksolid. The crude product was purified by normal phase chromatography togive 89B (0.66 g, 34% yield) as a dark brown solid. LC-MS (ESI) m/z:420.2 (M+H)⁺.

89C. tert-Butyl(1-(6-chloro-3-(4-nitro-2-(pent-4-enamido)phenyl)pyridazin-4-yl)but-3-en-1-yl)carbamate:To a solution of 89B (0.66 g, 1.572 mmol) in DCM (20 mL) were added TEA(0.438 mL, 3.14 mmol) and pent-4-enoyl chloride (0.208 mL, 1.886 mmol)at 0° C. The reaction was stirred under argon at 0° C. for 1.5 h. Thereaction mixture was diluted with DCM, washed with 1M HCl, saturatedNaHCO₃ and brine. The organic phase was dried over sodium sulfate,filtered and concentrated to give 89C (0.79 g, 100% yield) as a brownsolid. LC-MS (ESI) m/z: 502.2 (M +H)⁺.

89D. tert-Butyl(1-(3-(4-amino-2pent-4-enamido)phenyl)-6-chloropyridazin-4-yl)but-3-en-1-yl)carbamate:To a solution of 89C (0.79 g, 1.574 mmol) in methanol (30 mL) were addedzinc powder (0.515 g, 7.87 mmol) and ammonium chloride (0.842 g, 15.74mmol) at 0 ° C. The reaction was stirred under argon at rt for 4 h. Thesolid was filtered through a pad of CELITE® and the filtrate wasconcentrated to give 89D (0.74 g, 100% yield) as a dark brown solid.LC-MS (ESI) m/z: 472,4 (M+H)⁺.

89E.{4-[4-(1-tert-Butoxycarbonylamino-but-3-enyl)-6-chloro-pyridazin-3-yl]-3-pent-4-enoylamino-phenyl}-carbamicacid methyl ester: To a solution of 89D (0.74 g, 1568 mmol) in DCM (20mL) and DMF (2 mL)(to make it more soluble) were added pyridine (0.254mL, 3.14 mmol) and methyl chloroformate (0.121 mL, 1.568 mmol) at 0° C.The reaction was stirred under argon at 0° C. for 30 min. Water wasadded to quench the reaction. Most DCM was evaporated. The reactionmixture was diluted with EtOAc, washed with 1M HCl saturated NaHCO₃ andbrine. The organic phase was dried over MgSO₄, filtered andconcentrated. The crude product was purified by normal phasechromatography to give 89E (501 mg, 60% yield) as a brown solid. (LC-MS(ESI) m/z: 530.3⁺.

89F. (E)-tert-butyl methyl(3-chloro-11-oxo-5,6,9,10,11,12-hexahydrobenzo[b]pyridazino[3,4-d[1]azacyclododechie-5,14-diyl)dicarbamate:To a solution of 89E (350 mg, 0.660 mmol) in DCM (100 mL) was addedGrubbs (II) (168 mg, 0.198 mmol) at rt. The solution was purged withargon for 3 min and then was stirred under argon at reflux for 1 h.Solvent was removed. The residue was dissolved in EtOAc, which waswashed with water and brine Organic phase was dried over MgSO₄, filteredand concentrated to give a dark solid. The crude product was purified bynormal phase chromatography to give 89F (185 mg, 56% yield) as a brownsolid. LC-MS (ESI) m/z; 502.3 (M+H)⁺.

89G. Example 89 was prepared following the procedures described in step3C, by replacing 3B with 89F; followed by step1G. ¹H NMR (400 MHz,MeOD)δ ppm 9.48 (s. 1H), 8.67 (d, J=4.3 Hz, 1H), 8,14 (s, 1H), 8.00 (s,1H), 7.92 (s, 1H), 7.64 (dd, J =8.5, 1.9 Hz, 1H), 7.55 (d, J=8.6 Hz,1H), 7.45 (dd, J=14.0, 7.6 Hz, 1H), 7.07 (d, J=15.6 Hz, 1H), 6.59 (d,J=15.8 Hz, 1H), 5.34 - 5.11 (m, 2H), 4.58 - 4.36 (m, 1H), 3.76 (s, 3H),3.10 - 2.96 (m, 1H), 2.64 - 2.51 m, 1H), 2.19 (dd, J=17.9, 11.0 Hz,3H),1.30(t,J=7.3 Hz, 1H). LC-MS (ESI) m/z: 634.3 (M+H)⁺. AnalyticalHPLC: RT =7.596 min.

EXAMPLE 90{(E)-(S)-15-[(4-Aminomethyl-cyclohexanecarbonyl)-amino]-9-oxo-8,17-diaza-tricyclo[14.3.1.0^(2,7)]icosa-1(20),2(7),3,5,12,16,18-heptaen-5-yl}-carbamic acid methyl ester, 2 TFAsalt

Example 90 was prepared following the procedures described in step 3C,by replacing 3B with 88G; followed by steps 3B; and 3C. ¹H NMR (500 MHz,CD₃OD) δ ppm 8.70 (d, J=6.0 Hz, 1 H), 7.75 (dd, J=6.0, 1.6 Hz, 1 H),7.53-7.63 (m, 2 H), 7.49 (dd, J=8.8, 2.2 Hz, 1 H), 7.39 (d, J=8.2 Hz, 1H), 5.46-5.59 (m, 1 H), 5.36 (dd, J=15.7, 5.5 Hz, 1 H), 4.97 (dd, J=9.3,4.4 Hz, 1 H), 3.75 (s, 3 H), 2.77 (d, J=7.1 Hz, 2 H), 2.67-2.75 (m, 1H), 2.44-2.58 (m, 2 H), 2.30-2.44 (m, 4 H), 1.79-1.97 (m, 4 H),1.51-1.65 (m, 1 H), 1.32-1.50 (m, 2 H), 0.99-1.15 (m, 2 H). MS (ESI)m/z: 506.4 (M+H)⁺. Analytical HPLC (Method C): RT=6.97 min.

EXAMPLE 91{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,17-diaza-tricyclo[14.3.1.0^(2,7)]icosa-1(20),2(7),3,5,16,18-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

91A.((S)-15-Amino-9-oxo-8,17-diaza-tricyclo[14.3.1.0^(2,7)]icosa-1(20),2(7),3,5,16,18-hexaen-5-yl)-carbamicacid methyl ester, 2 TFA salt: Compound 91A was prepared following theprocedures described in step 2G, by replacing 2E/2F with 88G; followedby step 3C. MS (ESI) m/z: 369.1 (M+H)⁺.

91B. Example 91 was prepared following the procedure described in step1G, by replacing 1F with 91A. ¹H NMR (500 MHz, DMSO-d₆)) δ ppm 9.81 (s,1 H), 9.78 (s, 1 H), 9.36 (s, 1 H), 8.56 (d, J=4.9 Hz, 1 H), 8.53 (d,J=7.7 Hz, 1 H), 7.87 (d, J=1.6 Hz, 1 H), 7.66 (dd, J=8.8, 2.2 Hz, 1 H),7.64 (d, J=8.8 Hz, 1 H), 7.37-7.43 (m, 2 H), 7.28 (d, J=8.2 Hz, 1H),7.21 (dd, J=4.9, 1.1 Hz, 1H), 7.11 (s, 1H), 6.93 (d, J=15.4 Hz, 1 H),6.73 (d, J=15.9 Hz, 1 H), 4.76-4.83 (m, 1 H), 3.62 (s, 3 H), 2.09-2.20(m, 2 H), 1.76-1.88 (m, 1 H), 1.56-1.68 (m, 2 H), 1.30-1.42 (m, 1 H),1.07-1.26 (m, 3 H), 0.70-0.82 (m, 1 H). MS (ESI) m/z: 601.3 (M+H)⁺ and603.2 (M+2+H)⁺. Analytical HPLC (Method D): RT=4.56 min.

EXAMPLE 92 (E)-Methyl(5-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamido)-11-oxo-5,6,7,8,9,10,11,12-octahydrobenzo[b]pyridazino[3,4-d][1]azacyclododecin-14-yl)carbarnate

Example 92 was prepared by following the procedures described in step2G, by replacing 2E with 89F; followed by steps 3C; and 1G. ¹HNMR (400MHz, CD₃OD) δ ppm 9.44 (s, 1H),9.27 (d, J=5.4 Hz, 1H), 8.32 (d, J=1.5Hz, 1H), 7.99 (d, J=5.4 Hz, 1H), 7.85 (d, J=2.2 Hz, 1H), 7.65 -7.59 (m,1H), 7,55-7.48 (m, 2H), 7,23 (d, J=8.5 Hz, 1H), 6.91 (d, J=15.6 Hz, 1H),6.41 (d, J=15.7 Hz, 1H), 4.76-4.64 (m, 1H), 3.76 (s, 3H), 2.37-2.23 (m,2H), 2.04-1.91 (m, 1H), 1.82-1.70 (m, 1H), 1.58-1.17 (m, 6H). LC-MS(ESI) m/z: 602.3 (M+H)⁺. Analytical HPLC: RT 6.253 min.

EXAMPLE 93{(E)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8-aza-tricyclo[14.3.1.0^(2,7)]icosa-1(20),2,4,6,12,16,18-heptaen-5-yl}-carbamic acid methyl ester

93A. [1-(3-Bromo-phenyl)-but-3-enyl]-carbamic acid tert-butyl ester:Lithium hexamethyldisilazne solution (1M in THF, 7.30 mL, 7.3 mmol) wasadded to a cold (0° C.) THF (25 mL) solution of the 3-bromobenzaldehyde(1.33 g, 7.3 mmol) and stirred cold for 0.5 h. The reaction mixture wascooled to −78° C., followed by the addition of allyl MgBr (1M, 7.30 mL,7.3 mmol) dropwise. The cold reaction mixture was stirred at thistemperature for 1.5 h, than quenched with sat. NH₄Cl and graduallyallowed to warm up to room temperature. Extracted the organic materialswith EtOAc (2×100 mL), dried (MgSO₄) and evaporated to an oil (1.1 g).¹H NMR (400 MHz, CDCl₃) δ ppm 7.52 (s, 1H), 7.45-7.2 (m, 3H), 5.77-5.68(m, 1H), 5.15-5.09 (m, 2H), 3.99-3.95 (m, 1H), 2.49-2.30 (m, 2H). MS(ESI) m/z: 326.0 (M+H)⁺. The crude reaction mixture was dissolved indioxane (50 mL), and, to this was added Boc₂O (0.74g, 3.4 mmol) followedby the addition of TEA (1 mL) and subsequently stirred at roomtemperature overnight. Quenched the reaction mixture with water (100 mL)and the desired product was extracted with EtOAc (2×100 mL), dried(MgSO₄) and evaporated to a semi-solid mass which gradually solidified(1.25 g, 79%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.45-7.18 (m, 4H),5.66-5.61 (m, 1H), 5.17-5.08 (m, 2H), 4.89 (bs, 1H), 4.68 (bs, 1H), 2.48(bm, 2H), 1.41 (bs, 9H) ppm. MS (ESI) m/z: 3499 (M+Na)⁺.

93B. Example 93 was prepared following the procedures described in step88C, by replacing 88B with 93A; followed by steps 88E; 88F, by replacingmethanol with acetone and by replacing solid ammonium chloride with asaturated aqueous solution of ammonium chloride; 88G, by running thereaction without pTsOH; 3C; and

1G. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.77 (s, 1H), 9.68 (bs, 1H), 9.12(s, 1H), 8.61 (d, J=7.7 Hz, 1H), 7.98 (s, 1H), 7.66 (m, 2H), 7.40-7.10(m, 4H), 6.95 (s, 1H), 6.81 (q, 2H), 5.40-5.20, m, 2H), 4.78 (m, 1H),3.62 (s, 3H), 2.25 (m, 4H), 1.16 (m, 2H) ppm. MS (ESI) m/z: 598.4(M+H)⁺. Analytical HPLC: RT=7.851 min.

EXAMPLE 9416-Chloro-14-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-12-oxo-8-oxa-11,17,18-triaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaene-5-carboxylicacid methyl ester

94A.4-[5-(2-Benzyloxycarbonyl-1-tert-butoxycarbonylamino-ethyl)-6-chloro-pyridazin-3-yl]-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-benzoicacid methyl ester: To a solution of benzyl3-(tert-butoxycarbonylamino)-3-(3,6-dichloropyridazin-4-yl)propanoate(200 mg, 0.469 mmol) prepared by following a literature procedure(Cowden, C. J., Org. Lett., 4497-4499 (2003)) in dioxane (10 mL) wereadded Intermediate 13 (308 mg, 0.704 mmol), Cs₂CO₃ (382 mg, 1.173 mmol)and tri-tert-butylphosphine tetrafluoroborate (13.61 mg, 0.047 mmol).The solution was purged with argon for 2 min and then Pd₂dba₃ (21.48 mg,0.023 mmol) was added. The reaction was stirred under argon at 90° C.for 2 h. The solid was filtered-off and the solvent was removed. Thecrude mixture was purified by normal phase chromatography to give 94A(128 mg, 38% yield) as a yellow solid. LC-MS (ESI) m/z: 715.2 (M+H)⁺.

94B.4-[5-(1-tert-Butoxycarbonylamino-2-carboxy-ethyl)-6-chloro-pyridazin-3-yl]-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-benzoicacid methyl ester: To a solution of 94A (128 mg, 0.179 mmol) in MeOH (5mL) and ethyl acetate (5 mL) (more soluble in EtOAc) was added catalyticamount of 10% Pd/C. The reaction was stirred under a hydrogen balloon atrt for 3 h. The catalyst was filtered off and the solvent was removed togive 94B (102 mg, 91% yield) as a yellow solid. LC-MS (ESI) m/z: 625.2(M+H)⁺.

94C.3-(2-Amino-ethoxy)-4-[5-(1-tert-butoxycarbonylamino-2-carboxy-ethyl)-6-chloro-pyridazin-3-yl]-benzoicacid methyl ester, TFA salt: To a solution of 94B (102 mg, 0.163 mmol)in EtOH (5 mL) was added hydrazine (0.1 mL, 3.19 mmol) at rt. Thereaction was stirred under argon at reflux for 30 min. the solvent wasremoved. Purification by reverse phase chromatography gave 94C (25 mg,25.2% yield) as a solid. LC-MS (ESI) m/z: 495.1 (M+H)⁺.

94D.14-tert-Butoxycarbonylamino-16-chloro-12-oxo-8-oxa-11,17,18-triaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaene-5-carboxylicacid methyl ester: To a solution of BOP reagent (36.3 mg, 0.082 mmol),DIEA (0.036 mL, 0.205 mmol) and DMAP (5.02 mg, 0.041 mmol) in DCM (30mL) was added a solution of 94C (25 mg, 0.041 mmol) in DMF (2.0 mL)through a syringe pump over 2 h at rt. Upon addition, the reaction wasstirred for another 30 min and the solvent was removed. The crudeproduct was purified by reverse phase chromatography to give 94D (3.0mg, 15.32% yield) as a tan solid. LC-MS (ESI) m/z: 477.1 (M+H)⁺.

94E. Example 94 was prepared by following the procedures described instep 3C, by replacing 3B with 94D; followed by step 1G. ¹H NMR (400 MHz,DMF-d₇) 6 ppm 9.84 (1 H, s), 8.80 (1 H, d, J=8.03 Hz), 8.33 (1 H, s),8.19-8.28 (1 H, m), 8.11 (1 H, s), 7.83 (1 H, d, J=8.28 Hz), 7.73-7.80(4 H, m), 7.00-7.09 (1 H, m), 6.90-6.99 (1 H, m), 5.47-5.63 (1 H, m),4.24 (2 H, dd, J=5.65, 1.88 Hz), 3.94 (3 H, s), 3.61 (2 H, t, J=5.90Hz), 3.03-3.14 (2 H, m). LC-MS (ESI) m/z: 609.2 (M+H)⁺. Analytical HPLC:RT=7.620 min.

EXAMPLE 95{(E)-(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

95A.((E)-(S)-14-tert-Butoxycarbonylamino-9-oxo-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-5-yl)-carbamicacid methyl ester, 1 TFA salt: This compound was prepared following theprocedures described in step 88E, by replacing pent-4-enoic acid withbut-3-enoic acid; followed by steps 88F; and 88G. MS (ESI) m/z: 453.3(M+H)⁺.

95B. Example 95 was prepared following the procedures described in step3C, by replacing 3B with 95A; followed by step 1G. ¹H NMR (500 MHz,CD₃OD) δ ppm 9.65 (s, 1 H), 9.49 (s, 1 H), 8.64 (d, J=6.0 Hz, 1 H), 7.99(d, J=2.2 Hz, 1 H), 7.71 (dd, J=6.0, 1.6 Hz, 1 H), 7.66 (dd, J=8.8, 2.7Hz, 1 H), 7.63 (br. s., 1 H), 7.57 (d, J=8.2 Hz, 1 H), 7.46-7.52 (m, 2H), 7.38 (s, 1 H), 7.10 (d, J=15.4 Hz, 1 H), 6.83 (d, J=15.4 Hz, 1 H),5.79-5.90 (m, 1 H), 5.08 (dd, J=9.6, 4.1 Hz, 1 H), 4.89-4.99 (m, 1 H),3.76 (s, 3 H), 2.98 (dd, J=11.5, 8.8 Hz, 1 H), 2.75-2.89 (m, 2 H),2.40-2.53 (m, 1 H). MS (ESI) m/z: 585.3 (M+H)⁺. Analytical HPLC (MethodD): RT=5.07 min.

EXAMPLE 96{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

96A.((S)-14-Amino-9-oxo-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl)-carbamicacid methyl ester, 2 TFA salt: Compound 96A was prepared following theprocedures described in step 2G, by replacing 2E/2F with 95A; followedby step 3C. MS (ESI) m/z: 355.2 (M+H)⁺.

96B. Example 96 was prepared following the procedures described in step1G, by replacing 1F with 96A. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.66 (s, 1H), 9.49 (s, 1 H), 8.68 (d, J=6.0 Hz, 1 H), 8.04 (s, 1 H), 7.97 (d,J=1.6 Hz, 1 H), 7.80 (d, J=5.5 Hz, 1 H), 7.66 (dd, J=8.5, 1.9 Hz, 1 H),7.61 (d, J=8.2 Hz, 1 H), 7.54-7.58 (m, 2 H), 7.50 (dd, J=8.2, 1.6 Hz, 1H), 7.10 (d, J=15.4 Hz, 1 H), 6.79 (d, J=15.4 Hz, 1 H), 5.06-5.15 (m, 1H), 3.76 (s, 3 H), 2.47-2.56 (m, 1 H), 2.08-2.19 (m, 1 H), 1.63-2.02 (m,4 H), 1.33-1.44 (m, 1 H), 0.66-0.81 (m, 1 H). MS (ESI) m/z: 587.3(M+H)⁺. Analytical HPLC (Method D): RT=4.37 min.

EXAMPLE 113{(R)-16-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-14-oxa-8,18,20-triaza-tricyclo[15.2.1.0^(2,7)]icosa-1(19),2,4,6,17(20)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 113 was prepared following the procedures described in step 10D,by replacing 10C with 52F; followed by steps 2E/2F; 2G; 10H; and 1G. ¹HNMR (400 MHz, CD₃OD) δ ppm 9.59 (s, 1 H) 9.52 (s, 1 H) 7.97 (d, J=2.26Hz, 1 H) 7.77 (d, J=1.76 Hz, 1 H) 7.66-7.70 (m, 1 H) 7.56-7.61 (m, 1 H)7.45-7.48 (m, 1 H) 7.44 (d, J=2.01 Hz, 1 H) 7.36-7.42 (m, 1 H) 7.16 (d,J=15.81 Hz, 1 H) 6.80 (d, J=15.56 Hz, 1 H) 5.29 (t, J=4.14 Hz, 1 H)3.84-3.97 (m, 2 H) 3.75 (s, 3 H) 3.58-3.69 (m, 1 H) 3.43-3.55 (m, 1 H)2.26-2.44 (m, 2 H) 1.54-1.75 (m, 4 H). MS(ESI) m/z: 606.3(M+H)⁺.Analytical HPLC: RT=5.28 min.

EXAMPLE 115{(S)-16-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-14-oxo-8,13,18,20-tetraaza-tricyclo[15.2.1.0^(2,7)]icosa-1(19),2,4,6,17(20)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

Example 115 was prepared following the procedures described in Example79 by replacing benzyl 3-aminopropylcarbamate HCl salt with benzyl4-aminobutylcarbamate HCl salt in 79A. ¹H NMR (400 MHz, MeOD) δ ppm 9.52(1 H, s), 8.00 (1 H, d, J=2.26 Hz), 7.68 (1 H, dd, J=8.53, 2.26 Hz),7.57-7.62 (2 H, m), 7.54 (1 H, d, J=8.53 Hz), 7.51 (1 H, s), 7.19 (1 H,d, J=15.56 Hz), 7.15 (1 H, dd, J=8.53, 2.01 Hz), 6.77 (1 H, d, J=15.81Hz), 5.54 (1 H, dd, J=8.53, 5.02 Hz), 3.75 (3 H, s), 3.19-3.43 (4 H, m),2.80-2.93 (1 H, m), 1.56-1.81 (4 H, m). LC-MS (ESI) m/z: 605.2 (M+H)⁺.Analytical HPLC, RT=4.950 min.

EXAMPLE 116{(10R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-10-methyl-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamic acid methyl ester, 1TFA salt,diastereomer A

116A. A solution of Example 10C (5 g, 9.40 mmol) and triethylamine(1.564 ml, 11.28 mmol) in EtOAc (Volume: 30 ml) was cooled down to 0° C.under Ar, 2,2,2-trifluoroacetic anhydride (1.458 ml, 10.34 mmol) wasadded dropwise. After 1 hr, the reaction mixture was washed with waterand brine, dried over Na₂SO₄, filtered off solid, concentrated.Purification by normal phase chromatography gave 5.26 g (97%) of 116A asa pale yellow solid. MS (ESI) m/z: 628.1 (M+H)⁺.

116B. Benzyl 2-methylbut-3-enoate: To a solution of 2-methylbut-3-enoicacid (2 g, 18.98 mmol) in CH₂Cl₂ (38.0 ml) was added phenylmethanol(1.966 ml, 18.98 mmol), DCC (3.92 g, 18.98 mmol) and DMAP (0.232 g,1.898 mmol) (slight exotherm). The reaction was stirred at rt for fourhours. The reaction was filtered off solid, rinsed with hexane,concentrated. Purification by normal phase chromatography gave 3.55 g(98%) of 116B as a colorless oil.

116C. (6S,E)-Benzyl6-(tert-butoxycarbonylamino)-6-(4-(4-(methoxycarbonylamino)-2-(2,2,2-trifluoroacetamido)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-2-methylhex-3-enoate:A solution of 116A (0.841 g, 1.340 mmol) in DCM (Volume: 26.8 ml) wasadded pTsOH (0.255 g, 1.340 mmol). The reaction mixture was degassed bybubbling into Ar for 30 mins, then the mixture was stirred under Ar at40° C. for 40 mins, 116B (1.53 g, 8.04 mmol) was added, followed byGrubbs(II) (0.341 g, 0.402 mmol) in 2 ml degassed DCM dropwise. Thereaction was stirred at 40° C. overnight. The reaction was quenched withsat. aq. NaHCO₃, extracted with DCM, washed with brine, and dried theorganic layer over MgSO₄, filtered off solid, concentrated. Purificationby normal phase chromatography gave 522 mg (49%) of 116C as a lightbrownish oil. MS (ESI) m/z: 790.4 (M+H)⁺.

116D.(6S)-6-(tert-Butoxycarbonylamino)-6-(4-(4-(methoxycarbonylamino)-2-(2,2,2-trifluoroacetamido)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-2-methylhexanoicacid: A solution of 116C (810 mg, 1.025 mmol) in MeOH (20.5 ml) wasvacuumed and refilled with Ar, then Pd/C 10% wt (109 mg, 0.103 mmol) wasadded, vacuumed and refilled with H₂, stirred under H₂ balloon at rtovernight. The reaction mixture was filtered, rinsed and concentrated togive 116D as light greenish foam (709 mg, 99%) without furtherpurification. MS (ESI) m/z: 702.5 (M+H)⁺.

116E.(6S)-6-(4-(2-Amino-4-(methoxycarbonylamino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(tert-butoxycarbonylamino)-2-methylhexanoicacid: To a solution of 116D (709 mg, 1.010 mmol) in MeOH (10.100 ml) wasadded lithium hydroxide (2N aq) (3.54 ml, 7.07 mmol), sealed and heatedat 60° C. for 5 hr. The reaction was cooled down and concentrated. Theresidue was adjusted with 1N HCl in aq to pH˜6, extracted with EtOAcuntil no more product in aqueous layer. EtOAc layer washed with brine,dried over MgSO₄, filtered off solid, concentrated to give 116E as adark black foam (640 mg, 100%) and used in next step without furtherpurification. MS (ESI) m/z: 606.4 (M+H)⁺.

116F. To a solution of BOP (1.117 g, 2.53 mmol) and DMAP (0.518 g, 4.24mmol) in CH₂Cl₂ (Ratio: 25, Volume: 324 ml) and DMF (Ratio: 1.000,Volume: 12.95 ml) was added dropwise via syringe pump a solution of 116E(0.612 g, 1.010 mmol) and DIEA (1.235 ml, 7.07 mmol) in 8 ml DMF over 8hrs. Stirred at rt overnight. The reaction was transferred to a sealedbottle and heated at 60° C. for 5 hrs then cooled down to rt and stirredat rt over the weekend. MeOH was added to quench the reaction. Thereaction was concentrated, diluted with EtOAc, washed with H₂O (2×),brine, dried over MgSO₄, filtered and concentrated. Purification bynormal phase chromatography gave 116F (287 mg, 48%) as a light yellowsolid. Separation of 116F by reverse phase chromatography provided twodiastereomers.

116G.[(10R,14S)-5-Methoxycarbonylamino-10-methyl-9-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester: fast eluting isomer. MS (ESI) m/z: 588.3 (M+H)⁺.

116H.[(10S,14S)-5-Methoxycarbonylamino-10-methyl-9-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester: slow eluting isomer. MS (ESI) m/z: 588.3 (M+H)⁺.

116I. Example 116 was prepared following the procedures described in 1F,by replacing 1D with 116G; followed by 1G. ¹H NMR (400 MHz, CD₃OD) δ ppm9.51 (s, 1 H), 7.96 (d, J=2.2 Hz, 1 H), 7.67 (dd, J=8.8, 2.2 Hz, 1 H),7.58 (d, J=8.8 Hz, 2 H), 7.48-7.54 (m, 1 H), 7.41-7.48 (m, 2 H), 7.13(d, J=15.4 Hz, 1 H), 6.74 (d, J=15.9 Hz, 1 H), 5.02 (dd, J=10.4, 6.0 Hz,1 H), 3.75 (s, 3 H), 2.43-2.56 (m, 1 H), 2.16-2.29 (m, 1 H), 1.83-1.97(m, 1 H), 1.57 (d, J=9.3 Hz, 1 H), 1.21-1.36 (m, 2 H), 1.18 (d, J=7.1Hz, 3 H), 1.05-1.18 (m, 1 H). MS (ESI) m/z: 590.3 (M+H)⁺. AnalyticalHPLC: RT=4.16 min. (Method B).

EXAMPLE 117{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-11-methyl-9-oxo-8,11,16,18-tetraaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

117A.{3-Bromo-4-[2-((S)-1-tert-butoxycarbonylamino-3-oxo-propyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: To a solution of 10B (100 mg, 0.168 mmol) inacetonitrile (4.00 ml) were added water (1 ml), sodium periodate (144mg, 0.672 mmol) and osmium tetroxide (0.105 ml, 8.39 μmol) at 0° C. Thereaction mixture was stirred and allowed to warm slowly to rt, thendiluted with ethyl acetate, and washed with water and brine. The organicphase was dried over magnesium sulfate, filtered and concentrated to abrown solid. Normal phase chromatography gave 117A as a brown solid (50mg, 49.8% yield). MS (ESI) m/z: 631.5(M+H)⁺.

117B.({(S)-3-[4-(2-Bromo-4-methoxycarbonylamino-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-3-tert-butoxycarbonylamino-propyl}-methyl-amino)-aceticacid: To a solution of 117A (300 mg, 0.502 mmol) in DCE (6 mL) was added2-(methylamino)acetic acid (67.1 mg, 0.753 mmol) and 1 drop of aceticacid (0.01 mL, 0.175 mmol). The reaction mixture was sonicated andstirred at room temperature for 2 hours. Sodium triacetoxyborohydride(319 mg, 1.506 mmol) was added and the reaction was stirred at roomtemperature for 3 days. The reaction was quenched with saturated aqueoussodium bicarbonate. The aqueous layer was extracted with ethyl acetate.The combined organic layers were washed with brine and dried overmagnesium sulfate, filtered and concentrated to yield 117B. MS (ESI)m/z: 672.3(M+H)⁺.

117C. Example 117 was prepared following the procedure described in step10C alternate), by replacing 10B with 117B; followed by steps 20F; 10H;and 1G. ¹H NMR (400 MHz, MeOD-d₄) δ ppm 9.52 (s, 1 H) 7.97 (d, J=2.2 Hz,1 H) 7.67 (dd, J=8.53, 2.2 Hz, 1 H) 7.59 (m, 2 H) 7.55 (s, 1 H) 7.46 (s,1 H) 7.37 (dd, J=8.52, 2.2 Hz, 1 H) 7.19 (d, J=15.68 Hz, 1H) 6.69 (d,J=15.41 Hz, 1 H) 5.26 (brs, 1 H) 3.93 (m, 1 H) 3.75 (m, 4 H) 3.27 (m, 1H) 3.00 (m, 1 H) 2.82 (s, 3 H) 2.44 (br s, 1 H) 2.37 (br s, 1 H). MS(ESI) m/z: 591.3(M+H)⁺. Analytical HPLC: RT=4.48 min.

EXAMPLE 118{(10S,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-10-methyl-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamic acid methyl ester 1 TFA salt

Example 118 was prepared following the procedures described in step 1F,by replacing 1D with 116H; followed by step 1G. ¹H NMR (400 MHz, CD₃OD)δ ppm 9.51 (s, 1 H), 7.97 (d, J=2.2 Hz, 1 H), 7.68 (dd, J=8.5, 2.5 Hz, 1H), 7.56-7.62 (m, 2 H), 7.50 (d, J=8.2 Hz, 1 H), 7.45 (s, 1 H),7.35-7.42 (m, 1 H), 7.14 (d, J=15.4 Hz, 1 H), 6.75 (d, J=15.4 Hz, 1 H),5.14 (dd, J=9.9, 6.6 Hz, 1 H), 3.76 (s, 3 H), 2.68-2.80 (m, 1 H),2.12-2.26 (m, 1 H), 1.90-2.05 (m, 1 H), 1.51-1.72 (m, 3 H), 1.03 (d,J=7.1 Hz, 3 H), 0.70 (br. s., 1 H). MS (ESI) m/z: 590.3 (M+H)⁺.Analytical HPLC: RT=4.08 min. (Method B).

EXAMPLE 119{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-12-oxo-8,11,16,18-tetraaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

Example 119 was prepared following the procedures described in Example79 by replacing benzyl 3-aminopropylcarbamate HCl salt with benzyl2-aminoethylcarbamate in 79A. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.52 (1 H,s), 7.99 (1 H, d, J=2.26 Hz), 7.92 (1 H, d, J=1.51 Hz), 7.75 (1 H, d,J=8.53 Hz), 7.67 (1 H, dd, J=8.53, 2.26 Hz), 7.55-7.61 (2 H, m), 7.34 (1H, dd, J=8.53, 2.01 Hz), 7.21 (1 H, d, J=15.81 Hz), 6.76 (1 H, d,J=15.56 Hz), 5.48-5.64 (1 H, m), 3.78-3.93 (1 H, m), 3.77 (3 H, s),3.33-3.72 (3 H, m), 2.81 (2 H, d, J=7.03 Hz). LC-MS (ESI) m/z: 577.2(M+H)⁺. Analytical HPLC: RT=4.621 min.

EXAMPLE 120(E)-N-((E)-(S)-5-Amino-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylamide,2 TFA salt

Example 120 was prepared following the procedure described in step 10H,by replacing 10G with 39A and by running the reaction at 75° C. for 20h; followed by step 1G. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.52 (s, 1 H),7.97 (d, J=2.2 Hz, 1 H), 7.68 (dd, J=8.8, 2.2 Hz, 1 H), 7.58 (d, J=8.8Hz, 1 H), 7.31 (s, 1 H), 7.24 (d, J=8.2 Hz, 1 H), 7.14 (d, J=15.4 Hz, 1H), 6.71-6.80 (m, 3 H), 5.50-5.60 (m, 1 H), 5.35-5.44 (m, 1 H), 5.08(dd, J=9.9, 4.9 Hz, 1 H), 2.74-2.83 (m, 1 H), 2.31-2.61 (m, 5 H). MS(ESI) m/z: 530.2 (M+H)⁺. Analytical HPLC: RT=4.24 min.

EXAMPLE 121(E)-N-((E)-(S)-18-Chloro-9-oxo-10-oxa-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylamide,1 TFA salt

Example 121 was prepared following the procedure described in 17A, byreplacing 16A with Example 87. ¹H NMR (500 MHz, CD₃OD) δ ppm 2.48-2.60(m, 1 H), 2.81-2.93 (m, 1 H), 4.37 (br. s., 2 H), 5.05 (dd, J=10.5, 5.0Hz, 1 H), 5.60-5.73 (m, 1 H), 5.76-5.89 (m, 1 H), 6.77 (d, J=15.7 Hz, 1H), 7.16 (d, J=15.4 Hz, 1 H), 7.24 (d, J=8.0 Hz, 1 H), 7.40 (td, J=7.4,1.2 Hz, 1 H), 7.49 (td, J=7.8, 1.2 Hz, 1 H), 7.52-7.56 (m, 1 H), 7.59(d, J=8.5 Hz, 1 H), 7.68 (dd, J=8.5, 2.2 Hz, 1 H), 7.99 (d, J=1.9 Hz, 1H), 9.52 (s, 1 H) MS (ESI) m/z: 551.2 (M+H)⁺. Analytical HPLC: RT=7.25min.

EXAMPLE 122(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((S)-9-oxo-19-oxa-8,17,18-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16-hexaen-15-yl)-acrylamide,and(Z)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((S)-9-oxo-19-oxa-8,17,18-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16-hexaen-15-yl)-acrylamide

122A. (S)-tert-Butyl1-(2-(2-nitrobenzoyl)hydrazinyl)-1-oxopent-4-en-2-ylcarbamate: A mixtureof [(S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (0.500 g, 2.323mmol), HATU (1.060 g, 2.79 mmol), and DIPEA (1.623 mL, 9.29 mmol) in DCM(15 mL) was stirred at rt under nitrogen for 3 d. Reaction mixture wasdiluted with additional DCM, then washed with water, 5% aq. citric acid,sat'd aq. NaHCO₃ and brine, then dried over anhydrous Mg₂SO₄, filteredand evaporated. Residue was purified by normal phase chromatography toprovide the acylhydrazide (0.7 g, 79.6.0% yield). MS (ESI) m/z: 379.3(M+H)⁺; 323.3 (M+H-tBu)⁺; 279.3 (M+H-Boc)⁺.

122B. (S)-tert-Butyl1-(5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl)but-3-enylcarbamate: Into a150 mL pressure vessel was charged a solution of 122A (0.57 g, 1.506mmol) in anhydrous THF (30 mL), and Burgess reagent (1.077 g, 4.52 mmol)was added. The vessel was sealed under Ar, and the mixture was heated ina 75° C. oil bath with stirring behind a blast shield for 2 hrs.Reaction was cooled to room temperature, vented and then left standingat room temperature overnight. Reaction mixture was transferred to around bottom flask with the aid of a little MeOH and evaporated todryness. Residue was purified by silica gel chromatography to providethe oxadiazole product (0.327 g, 0.907 mmol, 60.2% yield) MS (ESI) m/z383.3 (M+Na)⁺305.3 (M+H-tBu)⁺.

122C. (S)-tert-Butyl1-(5-(2-aminophenyl)-1,3,4-oxadiazol-2-yl)but-3-enylcarbamate: 122B(0.325 g, 0.902 mmol) was dissolved in ethanol (4.5 mL) and iron powder(1.007 g, 18.04 mmol) was added. The mixture was stirred at roomtemperature for I-2 min then 0.1 M HCl (4.51 mL, 0.451 mmol) was added,and the reaction was heated with stirring under nitrogen in a 50° C. oilbath for 1.5 h. Reaction was cooled to room temperature and thenfiltered twice through a pad of CELITE® and solids washed with water,EtOH and EtOAc then discarded. Filtrate was evaporated and remainingaqueous was diluted with NaHCO₃ (to pH 8), and extracted 3× with EtOAc.Combined extracts were washed with saturated aq. NaHCO₃ solution andbrine, dried over anhydrous Na₂SO₄, filtered and evaporated to providethe amine as a white crystalline solid, (0.216 g, 0.654 mmol, 72.5%yield). MS (ESI) m/z: 331.4 (M+H)⁺; 275.3 (M+H-tBu)⁺; 231.3 (M+H-Boc)⁺.

122D. (S)-tert-Butyl1-(5-(2-pent-4-enamidophenyl)-1,3,4-oxadiazol-2-yl)but-3-enylcarbamate:122C was dissolved in DCM (3.5 mL) and pyridine (0.105 mL, 1.302 mmol)was added. The solution was cooled in an ice/salt water bath to ˜0° C.,then 4-pentenoyl chloride (0.072 mL, 0.651 mmol) was added dropwise withstirring under nitrogen. The resulting mixture was stirred at 0-5° C.for 1 h then allowed to warm to room temperature. After 2h, the reactionwas diluted with EtOAc and washed with water, 1M HCl, saturated aq.NaHCO₃ and brine, then dried over anhydrous Na₂SO₄, filtered andevaporated. Residue was purified by silica gel chromatography to providethe amide (0.242 g, 0.587 mmol, 90% yield). MS (ESI) m/z: 413.4 (M+H)⁺;357.3 (M+H-tBu)⁺; 313.4 (M+H-Boc)⁺.

122E.((E)-(S)-9-Oxo-19-oxa-8,17,18-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16-hexaen-15-yl)-carbamicacid tert-butyl ester; and((Z)-(S)-9-Oxo-19-oxa-8,17,18-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16-hexaen-15-yl)-carbamicacid tert-butyl ester: 122D (135 mg, 0.327 mmol) was divided betweenfive-20 mL microwave vials. The vials were then flushed with argon for10-15 min followed by addition of anhydrous DCM (4.8 mM) and Grubbs (II)(36 mol %). All operations were carried out under argon and the fullycharged vials were flushed for an additional few minutes with argon,then capped, sealed, and heated for 90 min at 75° C. in the microwavethen left standing overnight. Contents of the five vials were combinedand concentrated to remove DCM, redissolved in MeOH, filtered andpurified by reverse phase HPLC to provide the macrocyclic alkene as amixture of trans/cis isomers (34 mg, 27%). MS (ESI) m/z: 385.2 (M+H)⁺;329.1 (M+H-tBu)⁺.

122E. Example 122: 122E (34 mg, 0.088 mmol) was dissolved in DCM (2 mL)and TFA (0.5 mL, 6.49 mmol) was added. The resulting mixture was stirredat room temperature under N2 for ˜5 h, then stripped to dryness. Residuewas taken up in MeOH and stripped (2×) then dried on vacuum pump. Thecrude trifluoroacetic acid salt of the amine (MS (ESI) m/z: 285.2(M+H)⁺; 33 mg, 0.116 mmol) was dissolved in DMF (1 mL) and(E)-2,5-dioxopyrrolidin-1-yl3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylate (46 mg, 0.132 mmol) andDIPEA (0.1 mL, 0.573 mmol) were added. The resulting dark solution wasstirred under a blanket of argon overnight. Reaction mixture was dilutedwith water and extracted 3× with EtOAc. Combined extracts were washedwith 5% aq. citric acid soln, saturated aq. NaHCO₃ soln and brine, thendried over anhydrous sodium sulfate, filtered and evaporated. Residuewas suspended in MeOH, sonicated and filtered. Solid was dissolved in a1:1 mixture of DMSO/MeOH, filtered and purified by reverse phase HPLC toprovide the title compound (14 mg, 23%). MS (ESI) m/z: 517.3 (M+H)⁺ asan 5:1 mixture of the trans/cis double bond isomers as determined by nmrand HPLC. Analytical HPLC: major trans isomer: RT=7.53 min; minor isomerRT=7.41.

EXAMPLE 123{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,13,17,19-tetraaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

Example 123 was prepared following the procedures described in step117B, by replacing 117A with 4-oxobutanoic acid and by replacing2-(methylamino) acetic acid with 20B; followed by steps 20D; 10C(alternate); 20F; 2G; 1G; and 10H. ¹H NMR (400 MHz, MeOD-d₄) δ ppm 9.54(s, 1 H), 7.99 (d, J=2.2 Hz, 1 H), 7.69 (dd, J=8.8, 2.2 Hz, 1 H), 7.60(d, J=8.8 Hz, 1 H), 7.48-7.56 (m, 2 H), 7.44 (s, 1 H), 7.37-7.43 (m, 1H), 7.24 (d, J=15.9 Hz, 1 H), 6.69 (d, J=15.4 Hz, 1 H), 5.52 (dd, J=8.2,3.8 Hz, 1 H), 3.74 (s, 3 H), 3.42-3.61 (m, 2 H), 3.24-3.29 (m, 2 H),2.50-2.78 (m, 2 H), 2.02-2.33 (m, 2 H). MS (ESI) m/z: 591.3 (M+H)⁺.Analytical HPLC: RT=3.88 min. (Method B).

EXAMPLE 124(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((E)-(S)-5-fluoro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-acrylamide,1 TFA salt

Example 124 was prepared following the procedures described in step 2A,by replacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate 17;followed by steps 2B; 2C; 10C; 10D, by replacing with but-3-enoic acidwith pent-4-enoic acid; 2E; 10H; and 15D. ¹H NMR (500 MHz, CD₃OD) δ ppm2.33-2.62 (m, 5 H), 2.75-2.84 (m, 1 H), 5.05-5.12 (m, 1 H), 5.37-5.47(m, 1 H), 5.52-5.62 (m, 1 H), 6.76 (d, J=15.7 Hz, 1 H), 7.11-7.21 (m, 3H), 7.43 (br. s., 1 H), 7.50-7.56 (m, 1 H), 7.56-7.61 (m, 1 H),7.66-7.71 (m, 1 H), 7.97 (br. s., 1 H), 9.51 (br. s., 1 H). ¹⁹F NMR (471MHz, CD₃OD) δ ppm −111.20. MS (ESI) m/z: 533.1 (M+H)⁺. Analytical HPLC:RT=5.03 min.

EXAMPLE 125{(Z)-(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 125 was prepared following the procedures described in step 10D,by replacing but-3-enoic acid with pent-4-enoic acid; followed by steps2F; 10H, by running the reaction at 75° C.; and 1G. ¹H NMR (500 MHz, 50°C., CD₃OD) δ ppm 9.46 (s, 1 H), 7.95 (d, J=2.2 Hz, 1 H), 7.64-7.68 (m, 2H), 7.57 (d, J=8.2 Hz, 1 H), 7.41 (d, J=8.8 Hz, 1 H), 7.35 (dd, J=8.3,2.2 Hz, 1 H), 7.31 (s, 1 H), 7.18 (d, J=15.4 Hz, 1 H), 6.70 (d, J=15.4Hz, 1 H), 5.57-5.64 (m, 1 H), 5.42-5.50 (m, 1 H), 5.16-5.22 (m, 1 H),3.76 (s, 3 H), 2.87-2.97 (m, 1 H), 2.68-2.77 (m, 1 H), 2.47-2.64 (m, 2H), 2.31-2.43 (m, 2 H). MS (ESI) m/z: 588.2 (M+H)⁺. Analytical HPLC:RT=4.86 min.

EXAMPLE 126(E)-N-((E)-(S)-18-Chloro-5-fluoro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylamide,1 TFA salt

Example 126 was prepared following the procedure described in 17A, byreplacing 16A with Example 124. ¹H NMR (500 MHz, CD₃OD) δ ppm 2.31-2.50(m, 5 H), 2.66-2.74 (m, 1 H), 4.96 (dd, J=10.5, 4.4 Hz, 1 H), 5.30-5.40(m, 1 H), 5.50-5.59 (m, 1 H), 6.77 (d, J=15.4 Hz, 1 H), 7.11-7.18 (m, 3H), 7.48-7.53 (m, 1 H), 7.57 (d, J=8.5 Hz, 1 H), 7.67 (dd, J=8.5, 2.2Hz, 1 H), 7.98 (d, J=2.2 Hz, 1 H), 9.51 (s, 1 H). ¹⁹F NMR (471 MHz,CD₃OD) δ ppm −112.21. MS (ESI) m/z: 567.2 (M+H)⁺. Analytical HPLC:RT=7.41 min.

EXAMPLE 127{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-12-methyl-9-oxo-8,12,17,19-tetraaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

127A.[4-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-(2,2,2-trifluoro-acetylamino)-phenyl]-carbamicacid methyl ester: To a suspension of 10C (200 mg, 0.376 mmol) in DCM (3ml) at 0° C. was added triethylamine (0.157 ml, 1.128 mmol), followed bytrifluoroacetic anhydride (0.064 ml, 0.451 mmol). The reaction mixturewas allowed to stir at rt for 1 h, then diluted with EtOAc, washed with1 N HCl and brine, and dried over magnesium sulfate. The solvent wasremoved under reduced pressure to give 127A (271 mg, 0.432 mmol, 115%yield) as a yellow foam. MS (ESI) m/z: 628.5(M+H)⁺.

127B.[4-[2-((S)-1-tert-Butoxycarbonylamino-3-oxo-propyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-(2,2,2-trifluoro-acetylamino)-phenyl]-carbamicacid methyl ester: This compound was prepared following the proceduresdescribed in 117A, by replacing 10B with 127A. MS (ESI) m/z:630.4(M+H)⁺.

127C.3-({(S)-3-tert-Butoxycarbonylamino-3-[4-[4-methoxycarbonylamino-2-(2,2,2-trifluoro-acetylamino)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-propyl}-methyl-amino)-propionicacid: To a solution of 127B (97 mg, 0.154 mmol) in MeOH (2 ml) was added3-(methylamino)propanoic acid (23.83 mg, 0.231 mmol) and 1 drop aceticacid, then sodium cyanoborohydride (4.84 mg, 0.077 mmol) was added andthe reaction was stirred at rt overnight. The reaction was quenched withsat. sodium bicarbonate, extracted with EtOAc and washed the organiclayer with brine. The organic layer was dried over MgSO₄, filtered andconcentrated to give 127C (86 mg, 0.120 mmol, 78% yield) as a lightorange solid. MS (ESI) m/z: 717.5(M+H)⁺.

127D.[(S)-5-Methoxycarbonylamino-11-methyl-9-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-8,11,16,18-tetraaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester: To a mixture of 127C (86 mg, 0.120 mmol) inmethanol (3 mL) was added potassium carbonate (116 mg, 0.840 mmol). Theresulting mixture was stirred at rt for 1 h, then stored at −10° C. overthe weekend. Water (0.150 mL) and 1 N aq. sodium hydroxide (0.4 mL,0.400 mmol) were added and the reaction was heated to 50° C. for fourhours. Purification by reverse phase chromatography afforded 127D (41mg, 0.066 mmol, 55.0% yield) as a dark orange solid. MS (ESI) m/z:621.2(M+H)⁺.

127E. Example 127 was prepared following the procedures described instep 23E, by replacing 23D with 127D; followed by steps 10H; and 15D. ¹HNMR (500 MHz, CD₃OD) δ ppm 9.52 (1 H, s), 7.96 (1 H, d, J=2.5 Hz), 7.66(1 H, dd, J=8.5, 2.2 Hz), 7.58 (2 H, d, J=8.5 Hz), 7.53 (1 H, d, J=8.5Hz), 7.48 (1 H, s), 7.33 (1 H, dd, J=8.5, 2.2 Hz), 7.19 (1 H, d, J=15.7Hz), 6.69 (1 H, d, J=15.7 Hz), 5.40 (1 H, dd, J=7.4, 3.9 Hz), 3.71-3.78(3 H, m), 3.60 (1 H, br. s.), 3.39-3.49 (1 H, m), 3.01 (3 H, s),2.84-2.92 (2 H, m), 2.38-2.46 (2 H, m). MS (ESI) m/z: 605.4(M+H)⁺.Analytical HPLC: RT=4.55 min.

EXAMPLE 128{(E)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-17-fluoro-9-oxo-8-aza-tricyclo[14.3.1.0^(2,7)]icosa-1(20),2,4,6,12,16,18-heptaen-5-yl}-carbamic acid methyl ester

Example 128 was prepared following the procedures described in step 93A,by replacing 3-bromobenzaldehyde with 3-bromo-6-fluorobenzaldehyde;followed by steps 88C; 88E; 88F, by replacing methanol with acetone andby replacing solid ammonium chloride with a saturated aqueous solutionof ammonium chloride; 88G, by running the reaction without pTsOH; 3C;and 1G. ¹H NMR (400 MHz, MeOD/DMSO-d₆) δ ppm 9.38 (s, 1H), 8.60 (s, 1H),7.01 (d, J=2.0 Hz, 1H), 6.72-6.63 (dd, J=2.0 & 8.3 Hz, 3H), 6.63 (dd,J=2.0 & 8.2 Hz, 1H), 6.32-6.20 m, 5H), 6.09-6.05 (d, J=15.4 Hz, 1H),5.94-5.91 (d, J=15.6 Hz, 1H), 4.58 (m, 1H), 4.47 (m, 2H), 2.80 (s, 3H),1.67 (m, 1H), 1.51-1.46 (m, 4H) ppm. MS (ESI) m/z: 616.0 (M+H)⁺.Analytical HPLC: RT=8.55 min.

EXAMPLE 129{(E)-(S)-15-[(4-Aminomethyl-cyclohexanecarbonyl)-amino]-10,10-difluoro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

Example 129 was prepared following the procedures described in step 10D,by replacing but-3-enoic acid with 2,2-difluoropent-4-enoic acid;followed by steps 2E; 10H; 3B; and 3C. ¹H NMR (400 MHz, CD₃OD) δ ppm9.67 (s, 1 H), 7.58 (d, J=2.2 Hz, 1 H), 7.53 (dd, J=8.2, 2.2 Hz, 1 H),7.38-7.46 (m, 2 H), 5.66-5.80 (m, 1 H), 5.20-5.31 (m, 1 H), 4.99 (dd,J=11.0, 4.4 Hz, 1 H), 3.76 (s, 3 H), 2.73-3.00 (m, 5 H), 2.48-2.61 (m, 1H), 2.26-2.39 (m, 1 H), 1.83-2.00 (m, 3 H), 1.54-1.69 (m, 1 H),1.38-1.54 (m, 2 H), 1.01-1.19 (m, 2 H). MS (ESI) m/z: 531.3 (M+H)⁺.Analytical HPLC: RT=1.73 min. (Method B).

EXAMPLE 130(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((S)-5-fluoro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-15-yl)-acrylamide,1 TFA salt

Example 130 was prepared following the procedures step 2A, by replacing2-bromo-1-(2-bromophenyl)ethanone with Intermediate 17; followed bysteps 2B; 2C; 10C; 10D, by replacing with but-3-enoic acid withpent-4-enoic acid; 2F; 10G, by replacing the hydrogen balloon withhydrogen (55 psi); 10H; and 15D. ¹H NMR (500 MHz, CD₃OD) δ ppm 0.81-0.91(m, 1 H), 0.94-1.05 (m, 1 H), 1.41-1.60 (m, 2 H), 1.61-1.78 (m, 2 H),1.99-2.09 (m, 1 H), 2.16-2.24 (m, 1 H), 2.30-2.42 (m, 2 H), 5.03 (dd,J=10.2, 4.7 Hz, 1 H), 6.74 (d, J=15.7 Hz, 1 H), 7.10-7.19 (m, 2 H), 7.22(dd, J=9.5, 2.3 Hz, 1 H), 7.48 (s, 1 H), 7.55-7.62 (m, 2 H), 7.68 (dd,J=8.5, 2.2 Hz, 1 H), 7.97 (d, J=2.2 Hz, 1 H), 9.51 (s, 1 H). ¹⁹F NMR(471 MHz, CD₃OD) δ ppm −111.56. MS (ESI) m/z: 535.2 (M+H)⁺. AnalyticalHPLC: RT=5.18 min.

EXAMPLE 131{15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-17-fluoro-9-oxo-8-aza-tricyclo[14.3.1.0^(2,7)]icosa-1(20),2,4,6,16,18-hexaen-5-yl}-carbamic acid methyl ester

Example 131 was prepared following the procedures described in step 93A,by replacing 3-bromobenzaldehyde with 3-bromo-6-fluorobenzaldehyde;followed by steps 88C; 88E; 88F, by replacing methanol with acetone andby replacing solid ammonium chloride with a saturated aqueous solutionof ammonium chloride; 88G, by running the reaction without pTsOH; 2G, byreplacing the hydrogen balloon with hydrogen (55 psi); 3C, replacing TFAand DCM with 4M HCl in dioxane; and 1G. ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.83(s, 1H), 9.76(s, 1H), 9.20(s, 1H), 8.77(bs, 1H), 8.54(d, 1H),7.90(s, 1H), 7.73-7.69(m, 2H), 7.50-7.42(m, 2H), 7.29-7.23(m, 3H),6.83(s, 2H), 4.98(m, 1H), 3.69(s, 3H), 2.50-2.25(m, 4H), 1.90(m, 1H),1.7(m, 1H), 1.50-1.01(m, 4H). MS (ESI) m/z: 618.1 (M+Na)⁺. AnalyticalHPLC: RT=7.95 min.

EXAMPLE 132(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((E)-(S)-5-fluoro-9-oxo-8,17-diaza-tricyclo[14.3.1.0^(2,7)]icosa-1(20),2(7),3,5,12,16,18-heptaen-15-yl)-acrylamide, 1 TFA salt

132A. 2-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-phenylamine:This compound was prepared following the procedure described inIntermediate 12, by replacing 2-bromo-5-nitroaniline with2-bromo-5-fluoroaniline. MS (ESI) m/z: 224.3(M+H)⁺.

132B. 2-Methyl-propane-2-sulfinic acid{(S)-1-[4-(2-amino-4-fluoro-phenyl)-pyridin-2-yl]-but-3-enyl}-amide: Around bottom flask was charged with 88B (0.377 g, 1.314 mmol), 132A(0.586 g, 2.63 mmol), PdCl₂(dppf)-CH₂Cl₂Adduct (0.107 g, 0.131 mmol),and Potassium phosphate, tribasic (0.558 g, 2.63 mmol), then evacuatedand flushed with Ar three times. DMSO (6.57 mL) and water (0.118 mL,6.57 mmol) were added, and the reaction was once again evacuated andflushed with Ar three times. The reaction was heated at 90° C. for 2hours, then left at room temperature overnight. The reaction was dilutedwith water and extracted three times with EtOAc. The combined organiclayer was washed with water and brine, then dried over MgSO₄, filtered,and condensed to yield a brown residue. The crude residue wasredissolved in MeOH, filtered through a small pad of CELITE® andpurified by reverse phase chromatography. Fractions from main peak wereneutralized with saturated NaHCO₃, partially condensed to remove theMeOH, then extracted three times with EtOAc. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate, filtered, andevaporated to yield an orange residue, 132B (0.280 g, 0.775 mmol, 58.9%yield). MS (ESI) m/z: 362.3(M+H)⁺.

132C.((E)-(S)-5-Fluoro-9-oxo-8,17-diaza-tricyclo[14.3.1.0^(2,7)]icosa-1(20),2(7),3,5,12,16,18-heptaen-15-yl)-carbamicacid tert-butyl ester: This compound was prepared from 132B in foursteps by cleavage of the t-butylsulfinamide and introduction of aBoc-protection group, reduction of the nitro to the correspondinganiline, coupling with 4-pentenoic acid and subsequent RCM of theresulting diene, following the procedures described for compounds 88D,52D, 88E and 88G. MS (ESI) m/z: 412.3(M+H)⁺.

132D. Example 132 was prepared from 132C by removal of the Bocprotecting group and coupling to Intermediate 1, following theprocedures described in steps 3C and 1G. ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.85 (1 H, s) 9.46 (1 H, s) 8.64 (1 H, d, J=7.70 Hz) 8.61 (1 H, d,J=4.95 Hz) 7.97 (1 H, d, J=1.65 Hz) 7.69-7.76 (2 H, m) 7.40 (1 H, dd,J=7.97, 6.32 Hz) 7.28 (1 H, d, J=4.95 Hz) 7.17-7.25 (2 H, m) 7.06 (1 H,d, J=15.39 Hz) 7.01 (1 H, s) 6.81 (1 H, d, J=15.39 Hz) 5.44 (1 H, ddd,J=15.12, 7.42, 7.15 Hz) 5.22 (1 H, ddd, J=15.53, 5.22, 5.08 Hz)4.87-4.96 (1 H, m) 2.19-2.40 (6 H, m). MS (ESI) m/z: 544.3(M+H)⁺.Analytical HPLC: RT=6.18 min.

EXAMPLE 133(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((S)-5-fluoro-9-oxo-8,17-diaza-tricyclo[14.3.1.0^(2,7)]icosa-1(20),2(7),3,5,16,18-hexaen-15-yl)-acrylamide, 1 TFA salt

Example 133 was prepared from 132C by hydrogenation of the double bond,deprotection of the Boc-protecting group and coupling with Intermediate1, following the procedures described in steps 2G, 3C and 1G. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 9.84 (1 H, s) 9.50 (1 H, s) 8.67 (1 H, d,J=4.95 Hz) 8.62 (1 H, d, J=7.70 Hz) 7.94 (1 H, d, J=1.65 Hz) 7.69-7.77(2 H, m) 7.48 (1 H, dd, J=9.07, 6.32 Hz) 7.33 (1 H, dd, J=4.95, 1.65 Hz)7.21-7.28 (2 H, m) 7.15 (1 H, s) 6.99 (1 H, d, J=15.39 Hz) 6.79 (1 H, d,J=15.94 Hz) 4.88 (1 H, ddd, J=11.54, 7.42, 4.12 Hz) 2.21 (2 H, t, J=5.77Hz) 1.88 (1 H, dd, J=13.19, 9.34 Hz) 1.71 (2 H, t, J=12.09 Hz) 1.42 (1H, dd, J=13.74, 4.40 Hz) 1.32 (1 H, br. s.) 1.11-1.26 (2 H, m) 0.91 (1H, d, J=4.40 Hz). MS (ESI) m/z: 546.4(M+H)⁺. Analytical HPLC: RT=6.34min.

EXAMPLE 134(E)-N-((S)-18-Chloro-5-fluoro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-15-yl)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylamide,1 TFA salt

Example 134 was prepared following the procedure described in 17A, byreplacing 16A with Example 130. ¹H NMR (500 MHz, CD₃OD) δ ppm 0.81-0.94(m, 1 H), 1.04-1.21 (m, 1 H), 1.34-1.54 (m, 2 H), 1.63-1.72 (m, 2 H),1.90-2.01 (m, 1 H), 2.04-2.15 (m, 1 H), 2.28-2.38 (m, 2 H), 4.91-4.95(m, 1 H), 6.74 (d, J=15.4 Hz, 1 H), 7.10 (d, J=15.7 Hz, 1 H), 7.13-7.20(m, 2 H), 7.52-7.58 (m, 2 H), 7.64 (dd, J=8.5, 2.2 Hz, 1 H), 7.93 (d,J=2.5 Hz, 1 H), 9.49 (s, 1 H). ¹⁹F NMR (471 MHz, CD₃OD) δ ppm −112.04.MS (ESI) m/z: 569.2 (M+H)⁺. Analytical HPLC: RT=7.54 min.

EXAMPLE 135{(E)-(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

Example 135 was prepared following the procedures described in step 10C,by replacing ammonium hydroxide with but-3-enylamine and running thereaction at 90° C.; followed by steps 10E; 1F, by replacing ethanol withmethanol and running the reaction at 75° C.; and 1G. ¹H NMR (500 MHz,50° C., CD₃OD) δ ppm 9.47 (s, 1 H), 7.96 (d, J=1.6 Hz, 1 H), 7.79 (s, 1H), 7.66 (dd, J=8.8, 2.2 Hz, 1 H), 7.55-7.62 (m, 2 H), 7.41 (s, 1 H),7.30 (dd, J=8.2, 2.2 Hz, 1 H), 7.19 (d, J=15.4 Hz, 1 H), 6.77 (d, J=15.9Hz, 1 H), 5.87-5.96 (m, 1 H), 5.20-5.28 (m, 1 H), 5.13 (ddd, J=15.3,7.6, 7.4 Hz, 1 H), 3.77 (s, 3 H), 3.29-3.35 (m, 2 H), 2.54-2.68 (m, 2H), 2.43-2.50 (m, 2 H). MS (ESI) m/z: 560.2 (M+H)⁺. Analytical HPLC:RT=5.53 min.

EXAMPLE 136[(E)-(S)-18-Chloro-15-(4-cyano-benzoylamino)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]-carbamicacid methyl ester, 1 TFA salt

Example 136 was prepared following the procedure described in step 15D,by replacing 15C with 76B, by replacing Intermediate 2 with4-cyano-benzoic acid, by replacing Hunig's base with triethylamine andrunning the reaction at 55° C. ¹H NMR (400 MHz, DMSO-d₆, 1 drop of D₂O)δ ppm 8.01 (d, J=8.2 Hz, 2 H), 7.93 (d, J=8.8 Hz, 2 H), 7.45 (s, 1 H),7.29-7.37 (m, 2 H), 5.51 (ddd, J=15.3, 7.6, 7.4 Hz, 1 H), 5.22-5.32 (m,1 H), 5.07 (dd, J=9.9, 4.4 Hz, 1 H), 3.65 (s, 3 H), 2.19-2.61 (m, 6 H).MS (ESI) m/z: 519.0 (M+H)⁺. Analytical HPLC: RT=6.12 min.

EXAMPLE 137{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-11,12-dihydroxy-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt, Diastereomers A:B (1:1.3)

137A.[(S)-11,12-Dihydroxy-5-methoxycarbonylamino-9-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester, 1 TFA salt, Diastereomers A:B (1:1.3) and 137B.[(S)-11,12-Dihydroxy-5-methoxycarbonylamino-9-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester, 1 TFA salt, Diastereomer C: The content of 1 gsealed vial of OsO₄ was dissolved in 200 ml t-Butanol. The pale greensolution was treated with 3 drops of 30% H₂O₂, and allowed to remain atrt overnight. If the solution turned dark, the dropwise addition of 30%H₂O₂ was repeated, until the pale green persisted. Compound 10E (67 mg,0.117 mmol) in acetone (1.17 mL) was cooled down to 0° C. SubsequentlyH₂O (0.021 mL, 1.172 mmol), NMO (21.23 mg, 0.176 mmol) and osmiumtetroxide (0.293 mL, 5.86 μmol) were added. The reaction was stirred at0° C. and gradually warmed up to rt overnight. MgSO₄ was added to thereaction mixture. The solid was filtered off, rinsed with MeOH and thefiltrate was concentrated to yield a black crude product. Purificationby reverse phase chromatography provided 9 mg of 137A, as a mixtureDiastereomers A:B (1:1.3), as a white solid and 7 mg of 137B(Diastereomer C), as a white solid. For 137A: MS (ESI) m/z: 606.4(M+H)⁺. For 137B: MS (ESI) m/z: 606.4 (M+H)⁺.

137C. Example 137 was prepared following the procedures described instep 1F, by replacing 1D with 137A; followed by step 1G. MS (ESI) m/z:608.3 (M+H)⁺. Analytical HPLC: RT=3.90, 4.06 min, ratio 1.3:1. (MethodB).

EXAMPLE 138(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((S)-9-oxo-5,8,16-triaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-14-yl)-acrylamide, 2 TFA salt

138A. 2-Methyl-propane-2-sulfinic acid[(S)-1-(3′-amino-[4,4′]bipyridinyl-2-yl)-but-3-enyl]-amide: 088B (591mg, 2.483 mmol) in a microwave tube was added Dioxane (9 ml) andpotassium phosphate tribasic (2.483 ml, 4.97 mmol). The mixture wasdegassed by bubbling through Ar for several minutes.Tetrakis(triphenylphosphine)palladium (0) (191 mg, 0.166 mmol) was addedand continued to bubble for a few minutes. Capped and heated at 100° C.overnight. More Tetrakis(triphenylphosphine)palladium (0) (80 mg) wasadded and the reaction was heated at 100° C. for additional 5 hrs. Thereaction was cooled down to rt and concentrated to remove dioxane,diluted with EtOAc/H₂O, extracted 2 more times with EtOAc. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated. Purification by normal phase chromatography gave 350 mg(50%) of 138A as slightly brownish foam. MS (ESI) m/z: 345.2 (M+H)⁺.

138B. Example 138 was prepared following the procedures described instep 88D, by replacing 88C with 138A; followed by steps 88E, byreplacing pentenoic acid with but-3-enoic acid; 88G, by replacing 1.1eq. of pTsOH with 2.2 eq. of pTsOH; 2G; 3C; and 1G. ¹H NMR (400 MHz,CD₃OD) δ ppm 9.49 (1 H, s), 8.82 (1 H, d, J=5.5 Hz), 8.75 (1 H, d, J=5.5Hz), 8.62 (1 H, s), 7.98 (1 H, d, J=2.2 Hz), 7.87-7.95 (2 H, m), 7.74 (1H, dd, J=5.5, 2.2 Hz), 7.66 (1 H, dd, J=8.8, 2.2 Hz), 7.56 (1 H, d,J=8.8 Hz), 7.08 (1 H, d, J=15.4 Hz), 6.81 (1 H, d, J=15.4 Hz), 5.12 (1H, dd, J=11.0, 5.5 Hz), 2.47-2.59 (1 H, m), 2.04-2.18 (1 H, m),1.53-2.01 (5 H, m), 1.29-1.49 (1 H, m), 0.63 (1 H, none). MS (ESI) m/z:515.5 (M+H)⁺. Analytical HPLC: RT=4.17 min (Method B).

EXAMPLE 144 (E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((S)-9-oxo-6,8,16-triaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaen-14-yl)-acrylamide,2 TFA salt

Example 144 was prepared following the procedures described in step138A, by replacing tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-ylcarbamatewith tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylcarbamate;followed by steps 88D; 88E, by replacing pentenoic acid with but-3-enoicacid; 88G, by replacing 1.1 eq. of pTsOH with 2.2 eq. of pTsOH; 2G; 3C;and 1G. MS (ESI) m/z: 515.2(M+H)⁺.

EXAMPLE 145{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-11,12-dihydroxy-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt, Diastereomer C

Example 145 was prepared following the procedures described in step 1F,by replacing 1D with 137B; followed by step 1G. ¹H NMR (400 MHz, CD₃OD)δ ppm 9.51 (s, 1 H), 7.98 (d, J=2.2 Hz, 1 H), 7.69 (dd, J=8.8, 2.2 Hz, 1H), 7.56-7.62 (m, 2 H), 7.43-7.50 (m, 2 H), 7.38 (dd, J=8.8, 2.2 Hz, 1H), 7.13 (d, J=15.4 Hz, 1 H), 6.76 (d, J=15.4 Hz, 1 H), 5.10 (dd,J=10.4, 6.6 Hz, 1 H), 3.91-3.97 (m, 1 H), 3.75 (s, 3 H), 3.01 (m, 1 H),2.63 (dd, J=11.6, 3.3 Hz, 1 H), 2.42-2.58 (m, 2 H), 2.02-2.12 (m, 1 H).MS (ESI) m/z: 608.3 (M+H)⁺. Analytical HPLC: RT=4.21 min. (Method B).

EXAMPLE 152{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-12-hydroxy-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamic acid methyl ester, 1 TFA salt

152A.[(S)-11-Hydroxy-5-methoxycarbonylamino-9-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester: To a solution of 10E/10F (56 mg, 0.098 mmol) inTHF (1 mL) was added borane tetrahydrofuran complex (0.294 mL, 0.294mmol) at 0° C. dropwise. After addition, the ice water bath was removedand the reaction was warmed up to room temperature. After 2 hrs,reaction mixture was recooled to 0° C. and aqueous solution of sodiumacetate (0.653 mL, 1.959 mmol) was added. Hydrogen peroxide (0.300 mL,2.94 mmol) was added dropwise. After addition, the reaction was warmedup to room temperature and stirred at room temperature for 2 hrs. Thereaction was extracted with EtOAc twice. Combined EtOAc layer washedwith brine, dried over Na₂SO₄, filtered off solid, concentrated.Purification by reverse phase chromatography gave 152A (3.8 mg, paleyellow solid), 152B (3 mg, pale yellow solid) and 152C (7.8 mg, paleyellow solid).

152A: MS (ESI) m/z: 590.4 (M+H)⁺. Analytical HPLC(Method B): RT=6.09min.

152B: MS (ESI) m/z: 590.4 (M+H)⁺. Analytical HPLC(Method B): RT=6.17min.

152C: MS (ESI) m/z: 590.4 (M+H)⁺. Analytical HPLC(Method B): RT=6.44min.

152D. Example 152 was prepared following the procedures described instep 1F, by replacing 1D with 152A; followed by step 1G. ¹H NMR (500MHz, CD₃OD) δ ppm 9.50 (s, 1 H), 7.93-8.00 (m, 1 H), 7.67 (dd, J=8.5,2.5 Hz, 1 H), 7.55-7.60 (m, 2 H), 7.46-7.52 (m, 1 H), 7.42-7.46 (m, 1H), 7.41 (s, 1 H), 7.18 (d, J=15.7 Hz, 1 H), 6.72 (d, J=15.4 Hz, 1 H),5.11-5.18 (m, 1 H), 3.75 (s, 3 H), 3.19-3.27 (m, 1 H), 2.42-2.49 (m, 2H), 2.16-2.24 (m, 2 H), 1.86-1.95 (m, 1 H), 1.21-1.34 (m, 1 H). MS (ESI)m/z: 592.2 (M+H)⁺. Analytical HPLC: RT=3.76 min (Method B).

EXAMPLE 153(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((S)-5-fluoro-9-oxo-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl)-acrylamide,1 TFA salt

153A.((E)-(S)-5-Fluoro-9-oxo-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl)-carbamicacid tert-butyl ester: This compound was prepared from 132B by cleavageof the t-butylsulfinamide and introduction of a Boc-protection group,coupling with 3-butenoic acid and subsequent RCM of the resulting diene,following the procedures described for compounds 88D, 88E (replacingpentenoic acid with but-3-enoic acid), and 88G. MS (ESI) m/z:398.3(M+H)⁺.

153B. Example 153 was prepared from 153A by hydrogenation,Boc-deprotection and coupling to Intermediate 1 following the proceduresdescribed for compounds 2G, 3C and 1G. ¹H NMR (500 MHz, DMSO-d₆) δ ppm9.85 (1 H, s) 9.84 (1 H, s) 8.74 (1 H, d, J=6.60 Hz) 8.71 (1 H, d,J=5.23 Hz) 7.93 (1 H, d, J=2.20 Hz) 7.70-7.77 (2 H, m) 7.62-7.68 (2 H,m) 7.53 (1 H, d, J=4.40 Hz) 7.31 (1 H, td, J=8.46, 2.61 Hz) 7.11 (1 H,dd, J=9.77, 2.61 Hz) 6.93-6.99 (1 H, m) 6.81-6.86 (1 H, m) 4.99-5.06 (1H, m) 2.35 (1 H, dd, J=10.32, 6.74 Hz) 1.85-1.93 (1 H, m) 1.73-1.81 (1H, m) 1.61-1.73 (2 H, m) 1.48 (1 H, ddd, J=11.14, 6.74, 4.40 Hz) 1.21 (1H, dd, J=6.33, 4.40 Hz) 0.51-0.62 (1 H, m). MS (ESI) m/z: 532.2 (M+H)⁺.Analytical HPLC: RT=5.90 min.

EXAMPLE 154{(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-trifluoromethyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

154A.{4-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-[2,2,2-trifluoro-eth-(E)-ylideneamino]-phenyl}-carbamicacid methyl ester: To a solution of 10C (0.805 g, 1.514 mmol) in DCM(30.3 mL) was added 1-ethoxy-2,2,2-trifluoroethanol (0.436 g, 3.03mmol), 5 Å molecular sieves (5 g, 1.514 mmol) and p-toluenesulfonic acidmonohydrate (0.014 g, 0.076 mmol). The reaction was warmed to 40° C.After 2 days additional 1-ethoxy-2,2,2-trifluoroethanol (0.436 g, 3.03mmol) was added. After 12 days, the reaction was filtered through a 0.45micron GMF filter and the filter cake was rinsed with DCM. The filtratewas concentrated and then toluene (3 mL) was added and thenconcentrated. This process repeated one more time to afford 154A (0.926g, 100% yield) as a brown oil and as a mixture of diastereomers. MS(ESI) m/z: 612.6 (M+H)⁺. This was used in the next step without furtherpurification.

154B.[4-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-(1-trifluoromethyl-but-3-enylamino)-phenyl]-carbamicacid methyl ester: To a cooled (0° C.) solution of 154A (0.926 g, 1.514mmol) in THF (30 mL) was added allylmagnesium bromide (1M in Et₂O, 5.00mL, 5.00 mmol). After 30 min, the reaction was allowed to warm to rt.After 1.5 h, the reaction was quenched with sat. NH₄Cl. Then thereaction mixture was diluted with EtOAc, washed with water, brine, driedover Na₂SO₄, filtered and concentrated. Purification by normal phasechromatography afforded 154B (0.49 g, 49.5% yield) as a yellow solid andas a mixture of diastereomers. MS (ESI) m/z: 654.5 (M+H)⁺.

154C.[(9R,14S)-14-tert-Butoxycarbonylamino-9-trifluoromethyl-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]-carbamicacid methyl ester, 2 TFA salt (Diastereomer A) and 154D.[(9S,14S)-14-tert-Butoxycarbonylamino-9-trifluoromethyl-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]-carbamicacid methyl ester, 2 TFA salt (Diastereomer B). The ring-closingmethathesis products (a mixture of E- and Z-alkene isomers as well asdiastereomers at the alpha amine) were prepared following the proceduresdescribed in step 2E/2F, by replacing 2D with 154B. To a solution of thering-closing metathesis product (1.01 g, 1.614 mmol) in EtOAc (32.3 mL)was added TFA (0.249 mL, 3.23 mmol) and 10% palladium on carbon (0.172g, 0.161 mmol). The reaction vessel was pressurized with hydrogen to 55psi. After 3 days the reaction was stopped and the reaction was filteredthrough a 0.45 μm GMF and the catalyst was rinsed with MeOH. Thefiltrate was concentrated. Purification by reverse phase chromatographyafforded 0.074 g (5.4%) of 154 C (diastereomer A) and 0.410 g (30%) of154 D (diastereomer B). MS (ESI) m/z: 628.4 (M+H)⁺. Alternatively, thepalladium on carbon catalyst can be replaced with platinum oxide.

154E.((9R,14S)-14-Amino-9-trifluoromethyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl)-carbamicacid methyl ester. A high-pressure vial, with a teflon-coated screw cap,containing a slightly cloudy mixture of 154D (diastereomer B) (0.0590 g,0.069 mmol) and 2-amino-3-mercaptopropanoic acid (0.042 g, 0.345 mmol)in 4M HCl in dioxane (1.551 mL, 6.20 mmol) was warmed to 75° C. A whiteprecipitate forms overtime. After 1.5 h, the reaction was stopped andconcentrated to give a solid. The solid was dissolved in sat. NaHCO₃ andthen extracted with EtOAc (3×). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated to give 154E asa pale-yellow foam. MS (ESI) m/z: 398.1 (M+H)⁺.

154F. Example 154 was prepared following the procedure described in 15D,by replacing 15C with 154 E. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.50 (s, 1H), 7.94 (d, J=2.2 Hz, 1 H), 7.66 (dd, J=8.8, 2.2 Hz, 1 H), 7.57 (d,J=8.2 Hz, 1 H), 7.50 (s, 1 H), 7.34 (s, 1 H), 7.27 (d, J=8.2 Hz, 1 H),7.06-7.14 (m, 2 H), 6.76 (d, J=15.4 Hz, 1 H), 5.13 (t, J=7.1 Hz, 1 H),3.73 (s, 3 H), 2.93-3.01 (m, 1 H), 2.34-2.43 (m, 1 H), 1.95-2.04 (m, 1H), 1.62-1.75 (m, 2 H), 1.48-1.59 (m, 2 H), 1.35-1.46 (m, 1 H),0.48-0.59 (m, 1 H). ¹⁹F NMR (470 MHz, CD₃OD) δ ppm −75.22. MS (ESI) m/z:630.4 (M+H)⁺. Analytical HPLC: RT=6.13 min.

Alternatively, 10C can be condensed with 1-ethoxy-2,2,2-trifluoroethanolto give the 154G rather than the imine (154A) according to the followingprocedure. Compound 154G can replace 154A in step 154B.

154G.[4-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-(1-ethoxy-2,2,2-trifluoro-ethylamino)-phenyl]-carbamicacid methyl ester: To a clear, dull yellow solution of 10C (2.0 g, 3.76mmol) in EtOH (7.52 mL) was added 1-ethoxy-2,2,2-trifluoroethanol (1.734ml, 15.05 mmol). The reaction was heated at 120° C. in a microwave for 3h. The reaction was cooled to RT and then the reaction was concentrated.Purification by normal phase chromatography gave 1.75 g (66%) of 154A,as an orange foam and as a mixture of diastereomers. MS (ESI) m/z: 658.4(M+H)⁺.

EXAMPLE 155{(9S,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-trifluoromethyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

155A.(9S,14S)-14-Amino-9-trifluoromethyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl)-carbamicacid methyl ester. Compound 155A was prepared following the proceduredescribed in 154E, by replacing 154D with 154C (diastereomer A). MS(ESI) m/z: 398.1 (M+H)⁺.

155B. Example 155 was prepared following the procedure described in 15D,by replacing 15C with 155A. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.51 (s, 1 H),7.98 (d, J=2.2 Hz, 1 H), 7.68 (dd, J=8.5, 2.5 Hz, 1 H), 7.58 (d, J=8.8Hz, 1 H), 7.54 (s, 1 H), 7.39 (s, 1 H), 7.31 (d, J=8.2 Hz, 1 H),7.09-7.18 (m, 2 H), 6.76 (d, J=15.4 Hz, 1 H), 5.24 (dd, J=11.0, 7.1 Hz,1 H), 3.75 (s, 3 H), 2.90-2.99 (m, 1 H), 2.24-2.37 (m, 1 H), 1.97-2.08(m, 1 H), 1.67-1.84 (m, 2 H), 1.43-1.63 (m, 3 H), 0.30-0.42 (m, 1 H).¹⁹F NMR (470 MHz, CD₃OD) δ ppm −74.66. MS (ESI) m/z: 630.4 (M+H)⁺.Analytical HPLC: RT=6.29 min.

EXAMPLE 156{(S)-17-Chloro-14-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

Example 156 was synthesized according to the procedure described inExample 7, by replacing Example 6 with Example 11. ¹H NMR (500 MHz,CD₃OD) δ ppm 9.54 (s, 1 H), 8.02 (d, J=2.5 Hz, 1 H), 7.91 (br. s., 1 H),7.84 (d, J=8.8 Hz, 1 H), 7.69 (dd, J=8.5, 2.2 Hz, 1 H), 7.61 (d, J=8.5Hz, 1 H), 7.32 (dd, J=8.5, 2.2 Hz, 1 H), 7.26 (d, J=15.7 Hz, 1 H), 6.81(d, J=15.7 Hz, 1 H), 5.20 (dd, J=11.0, 6.3 Hz, 1 H), 3.72 (s, 3 H),3.18-3.25 (m, 1 H), 2.92-3.00 (m, 1 H), 1.97-2.19 (m, 3 H), 1.82-1.90(m, 1 H), 1.62-1.72 (m, 2 H), 1.33-1.43 (m, 1 H), 0.76-0.87 (m, 1 H). MS(ESI) m/z: 596.5 (M+H)⁺. Analytical HPLC: RT=6.01 min.

EXAMPLE 159{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-ylmethyl}-carbamicacid methyl ester, TFA salt

159A. 3-Amino-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-benzonitrile:This compound was prepared following the procedures described forIntermediate 12, by replacing 2-bromo-5-nitroaniline with3-amino-4-bromobenzonitrile. MS (ESI) m/z: 163.1(M+H)⁺.

159B.((E)-(S)-5-Cyano-9-oxo-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl)-carbamicacid tert-butyl ester: This compound was prepared from 159A in foursteps by Suzuki coupling to 88B, cleavage of the t-butylsulfinamide andintroduction of a Boc-protection group, coupling with 3-butenoic acidand subsequent RCM of the resulting diene, following the proceduresdescribed for compounds 88C, 88D, 88E (substituting 3-butenoic acid for4-pentenoic acid), and 88G. MS (ESI) m/z: 405.2(M+H)⁺.

159C.((S)-5-Aminomethyl-9-oxo-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl)-carbamicacid tert-butyl ester: 155B (0.023 g, 0.057 mmol) was dissolved in MeOH(2.0 mL) and transferred to a flask containing a suspension of 10% Pd/Cin I-2 mL MeOH under argon. The mixture was evacuated and back-filledwith Ar 3×, then stirred under 1 atm of hydrogen for 3 days. Thecatalyst was removed by filtration through CELITE® and washed with MeOH;the filtrate was condensed to yield 155C (0.023 g, 99%), MS (ESI) m/z411.3(M+H)⁺.

159D.[(S)-5-(Methoxycarbonylamino-methyl)-9-oxo-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]-carbamicacid tert-butyl ester: 155C (0.023 g, 0.056 mmol) was dissolved inCH₂Cl₂ (0.5 mL), and TEA (0.016 mL, 0.112 mmol) was added. This mixturewas stirred under Ar in an ice/salt water bath. Methyl chloroformate(4.56 μL, 0.059 mmol) was added dropwise to the cold mixture. Thereaction was allowed to gradually assume room temperature over 2 hoursas the ice bath melted. The reaction was quenched with water and dilutedwith EtOAc. The organic layer was then washed with saturated NaHCO₃ andbrine, dried briefly over anhydrous MgSO₄, filtered and evaporated toyield 159D as a light yellow glass (0.017 g, 64.8%). MS (ESI) m/z:469.3(M+H)⁺.

159E. Example 159 was prepared from 159D by Boc-deprotection andcoupling with Intermediate 1, following the procedures described forsteps 3C and 1G. ¹H NMR (500 MHz, MeOD) δ ppm 9.48 (1 H, s) 8.71 (1 H,d, J=5.78 Hz) 7.97 (2 H, d, J=1.93 Hz) 7.77 (1 H, dd, J=5.64, 1.51 Hz)7.62-7.69 (2 H, m) 7.57 (1 H, d, J=8.53 Hz) 7.42 (1 H, d, J=7.98 Hz)7.23 (1 H, s) 7.10 (1 H, d, J=15.68 Hz) 6.79 (1 H, d, J=15.68 Hz) 5.11(1 H, dd, J=10.87, 5.64 Hz) 4.36 (2 H, s) 3.67 (3 H, s) 2.46-2.53 (1 H,m) 2.07-2.18 (1 H, m) 1.83-2.00 (2 H, m) 1.70-1.81 (1 H, m) 1.60-1.70 (1H, m) 1.35-1.44 (1 H, m) 0.70-0.81 (1 H, m). MS (ESI) m/z: 601.3 (M+H)⁺.Analytical HPLC: RT=5.54 min.

EXAMPLE 160{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-11-hydroxy-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamic acid methyl ester, 1 TFA salt

Example 160 was prepared following the procedures described in step 1F,by replacing 1D with 152B; followed by step 1G. ¹H NMR (500 MHz, CD₃OD)δ ppm 9.49 (s, 1 H), 7.91-8.01 (m, 1 H), 7.65-7.72 (m, 1 H), 7.55-7.63(m, 2 H), 7.43-7.52 (m, 2 H), 7.34-7.43 (m, 1 H), 7.15 (d, J=15.7 Hz, 1H), 6.73 (d, J=15.7 Hz, 1 H), 5.08-5.19 (m, 1 H), 3.85-3.95 (m, 1 H),3.76 (s, 3 H), 2.68-2.76 (m, 1 H), 2.40-2.54 (m, 1 H), 2.12-2.23 (m, 1H), 1.93-2.06 (m, 1 H), 1.39-1.51 (m, 1 H), 1.21-1.34 (m, 1 H). MS (ESI)m/z: 592.2 (M+H)⁺. Analytical HPLC: RT=3.86 min (Method B).

EXAMPLE 161{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-11-hydroxy-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamic acid methyl ester, 1 TFA salt

Example 161 was prepared following the procedures described in step 1F,by replacing 1D with 152C; followed by step 1G. ¹H NMR (500 MHz, CD₃OD)δ ppm 9.52 (s, 1 H), 7.92-8.04 (m, 1 H), 7.64-7.72 (m, 1 H), 7.56-7.63(m, 2 H), 7.50-7.56 (m, 1 H), 7.41-7.49 (m, 2 H), 7.17 (d, J=15.4 Hz, 1H), 6.77 (d, J=15.4 Hz, 1 H), 5.26-5.38 (m, 1 H), 3.76 (s, 3 H),3.63-3.72 (m, 1 H), 2.51-2.64 (m, 1 H), 2.30-2.44 (m, 2 H), 1.95-2.05(m, 1 H), 1.65-1.78 (m, 1 H), 1.30-1.47 (m, 1 H). MS (ESI) m/z: 592.2(M+H)⁺. Analytical HPLC: RT=3.69 min (Method B).

EXAMPLE 167{(E)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-17-methyl-9-oxo-8,16,18-triaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,11,15,17-heptaen-5-yl}-carbamicacid methyl ester

167A. (S)-4-tert-Butoxycarbonylamino-3-oxo-hept-6-enoic acid ethylester. To a solution of (S)-2-(tert-butoxycarbonylamino)pent-4-enoicacid (5.0g, 23.23 mmol) in THF (40 mL) was added carbonyldiimide (4.52g, 27.9 mmol) at rt. The reaction was stirred under argon at rt for 5 h.To another flask containing a solution of 3-ethoxy-3-oxopropanoic acid(4.60 g, 34.8 mmol) in THF (40 mL) was added dropwise isopropylmagnesiumchloride (34.8 mL, 69.7 mmol) at 0° C. Following the addition, thereaction was stirred at 0° C. for 30 min, at rt for 30 min and then at48° C. for 30 min. The reaction was cooled to rt and transferred to thecooled solution (0° C.) prepared in the first flask to give a milkysuspension. The reaction was allowed to stir at rt over night. Thereaction mixture was slowly poured into 1.0N HCl (200 ml) at 0° C. andgas was evolved. The reaction mixture was extracted with EtOAc, washedwith sat NaHCO₃ and brine. The organic phase was dried over sodiumsulfate, filtered and concentrated to give a clear colorless oil. Thecrude product was purified by normal phase chromatography to give 167A(5.36 g, 81% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm5.61-5.78 (1 H, m), 5.17 (1 H, d, J=3.26 Hz), 5.13 (2 H, d, J=2.26 Hz),4.32-4.50 (1 H, m), 4.20 (2 H, q, J=7.28 Hz), 3.47-3.64 (2 H, m),2.52-2.70 (1 H, m), 2.35-2.52 (1 H, m), 1.44 (9 H, s), 1.28 (3 H, t,J=7.15 Hz). MS (ESI) m/z: 308.1 (M+Na)⁺.

167B. [1-(6-Hydroxy-2-methyl-pyrimidin-4-yl)-but-3-enyl]-carbamic acidtert-butyl ester. To a solution of acetimidamide HCl salt (0.928 g, 9.81mmol) in MeOH (30 mL) were added sodium methoxide solution (25% wt/wt,4.49 mL, 19.63 mmol) and a solution of 167A (2.0g, 7.01 mmol) dissolvedin MeOH (15 mL) at rt. The reaction was stirred under argon at rt for 3h. The reaction was neutralized with 1.0 N HCl. Most solvent wasremoved. The reaction mixture was extracted with chloroform. The organicphase was washed with brine and dried over sodium sulfate, filtered andconcentrated. The crude product was purified by normal phasechromatography to give 167B (1.82 g, 93% yield) as a white solid. MS(ESI) m/z: 280.1 (M+H)⁺.

167C. [1-(6-Chloro-2-methyl-pyrimidin-4-yl)-but-3-enyl]-carbamic acidtert-butyl ester. To a flask containing 167B (1.82 g, 6.52 mmol) wasadded POCl₃ (12.15 mL, 130 mmol) at rt. The suspension was stirred underargon at 50° C. and the suspension turned a clear light brown solution.After 2 h, excess POCl₃ was removed under reduced pressure and theresidue was co-evaporated twice with toluene to give a dark tar. Thisintermediate was dissolved in acetonitrile (30 mL), to which were addedNa₂CO₃ (3.46 g, 32.6 mmol) and BOC₂O (1.817 mL, 7.82 mmol) at 0° C. Thereaction was stirred under argon at 0° C. for 1.5 h. The reactionmixture was diluted with EtOAc, washed with H₂O and brine. The organicphase was dried over sodium sulfate, filtered and concentrated. Thecrude product was purified by normal phase chromatography to give 167C(0.65 g, 34% yield) as a light yellow solid. ¹H NMR (400 MHz, CD₃OD) δppm 7.30 (1 H, s), 5.70-5.88 (1 H, m, J=17.13, 10.16, 6.93, 6.93 Hz),5.02-5.15 (2 H, m), 4.63 (1 H, dd, J=8.28, 5.27 Hz), 2.64 (3 H, s),2.54-2.62 (1 H, m), 2.36-2.49 (1 H, m), 1.43 (9 H, s). MS (ESI) m/z:298.1 (M+H)⁺.

167D.{3-But-3-enoylamino-4-[6-(1-tert-butoxycarbonylamino-but-3-enyl)-2-methyl-pyrimidin-4-yl]-phenyl}-carbamicacid methyl ester: This compound was prepared following the proceduresdescribed in step 88C, by replacing 88B with 167C; followed by steps88E; and 88F. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.23 (1 H, s), 7.63-7.72 (2H, m), 7.40 (1 H, s), 5.92-6.07 (1 H, m, J=17.07, 10.10, 7.00, 7.00 Hz),5.61-5.72 (1 H, m), 5.19-5.30 (2 H, m), 5.08 (2 H, d, J=12.05 Hz),4.62-4.78 (1 H, m), 3.75 (3 H, s), 3.18 (2 H, d, J=7.03 Hz), 2.73 (3 H,s), 2.45-2.64 (2 H, m), 1.40 (9 H, br. s.). MS (ESI) m/z: 496.1 (M+H)⁺.

167E.((E)-5-Methoxycarbonylamino-17-methyl-9-oxo-8,16,18-triaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,11,15,17-heptaen-14-yl)-carbamic acid tert-butyl ester. Asolution of 167D (25 mg, 0.050 mmol) in DCM (100 mL) was purged withargon and then was added 4 M HCl in dioxane (0.1 mL, 0.400 mmol) at rt.The solution was heated up to reflux and then Grubbs (II) catalyst(17.13 mg, 0.020 mmol) was added. The reaction was stirred under argonat reflux for 4 h. The reaction was cooled to rt and solvent wasremoved. Purification by reverse phase chromatography gave 167E (5.1 mg,22% yield) as a dark brown solid. MS (ESI) m/z: 468.0 (M+H)⁺.

167F. Example 167 was prepared following the procedures described instep 3C, by replacing 3B with 167E; followed by step 1G. ¹H NMR (400MHz, CD₃OD) δ ppm 9.55 (1 H, s), 9.50 (1 H, s), 8.01 (1 H, d, J=2.26Hz), 7.66 (1 H, dd, J=8.53, 2.26 Hz), 7.59-7.63 (2 H, m), 7.56 (1 H, d,J=8.53 Hz), 7.48 (1 H, dd, J=8.66, 2.13 Hz), 7.11 (1 H, d, J=15.56 Hz),6.96 (1 H, s), 6.89 (1 H, d, J=15.56 Hz), 5.74-5.85 (1 H, m), 4.96-5.03(2 H, m), 3.76 (3 H, s), 3.00 (1 H, dd, J=11.80, 9.29 Hz), 2.75-2.85 (2H, m), 2.74 (3 H, s), 2.21-2.33 (1 H, m). MS (ESI) m/z: 600.1 (M+H)⁺.Analytical HPLC: RT=6.383 min.

EXAMPLE 168

168A. Methyl 4-amino-2-nitrobenzoate: A suspension of4-amino-2-nitrobenzoic acid (1.0 g, 5.49 mmol) in MeOH (25 mL) wascooled in an ice/salt water bath with stirring under nitrogen whileSOCl₂ (0.601 mL, 8.24 mmol) was slowly added dropwise. The resultingamber solution was heated at reflux overnight. Reaction was cooled toroom temperature and evaporated to remove MeOH. Residue was partitionedbetween EtOAc and sat'd aq. NaHCO₃ solution, and aq. layer reextracted2× with EtOAc. Combined organic extracts were washed with brine, driedover anh. Na₂SO₄, filtered and evaporated to give the ester as ayellow-orange solid (0.95 g, 88%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.61(1 H, d, J=8.53 Hz) 6.83 (1 H, d, J=2.20 Hz) 6.74 (1H, dd, J=8.67, 2.34Hz) 6.54 (2 H, s) 3.72 (3 H, s).

168B. Methyl 4-(hydrazinecarbonyl)-3-nitrophenylcarbamate: 168A (0.94 g,4.79 mmol) was suspended in DCM (25 mL), pyridine (0.775 mL, 9.58 mmol)was added, and the mixture was cooled in an ice bath with stirring undernitrogen. Methylchloroformate (0.390 mL, 5.03 mmol) was then addeddropwise to the cold mixture. Stirring was continued for ˜30 min in theice bath then at room temperature for 4 h. Reaction was diluted withadditional DCM, washed 2× with 1M HCl, water and brine, then dried overanh. Na₂SO₄, filtered and evaporated to a light orange solid. The solidobtained (1.2 g, 4.72 mmol) was suspended in ethanol (24 ml), andhydrazine (2.4 ml, 76 mmol) was added. The mixture was heated at refluxunder nitrogen with stirring overnight in an 80° C. oil bath, thencooled to room temperature and filtered. Pale yellow solid was washedwith EtOH and Et₂O then air-dried. The filtrate was evaporated andresidue suspended in EtOAc/H₂O. Solid which separated was collected byfiltration, washed with EtOAc and Et₂O, dried and combined with initialsolid. The crude hydrazide was suspended in MeOH and sonicated for10-15, insoluble solid removed by filtration and washed with MeOH.Evaporation of the filtrate gave the product, 168B, as a bright yellowsolid. (0.363 g, 30.2%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.28 (1 H, s)9.60-9.71 (1 H, m) 8.13 (1 H, d, J=1.93 Hz) 7.71 (1 H, dd, J=8.39, 2.06Hz) 7.51 (1 H, d, J=8.53 Hz) 4.45 (2 H, d, J=4.13 Hz) 3.72 (3 H, s).

168C.{4-[5-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1,3,4-oxadiazol-2-yl]-3-nitro-phenyl}-carbamicacid methyl ester: 168B (0.3 g, 0.393 mmol) and(S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (0.085 g, 0.393 mmol)were dissolved in DMF (2 mL) in a 15 mL rbf and TEA (0.274 mL, 1.967mmol) was added. Mixture was stirred under nitrogen at room temperaturewhile propane phosphonic acid anhydride (T3P), 50% in EtOAc (0.293 mL,0.983 mmol) was added dropwise. The flask was fitted with a refluxcondenser, and the resulting mixture was stirred in an 80° C. oil bathfor 5 h. Reaction mixture was poured into ice water and extracted 3×with EtOAc. Combined extracts were washed with sat'd aq. NaHCO₃, waterand brine, dried over anh. Na₂SO₄, filtered and evaporated to provide{4-[N′—((S)-2-tert-butoxycarbonylamino-pent-4-enoyl)-hydrazinocarbonyl]-3-nitro-phenyl}-carbamicacid methyl ester, (0.46 g, 86%) as a light yellow solid which was usedwithout further purification. The solid (0.46 g, 1.019 mmol) wasdissolved in anhydrous THF (20 mL) under argon and the solutiontransferred to a 75 mL pressure flask. Burgess reagent (1.33 g, 5.58mmol) was added, the flask was sealed with a pressure relief cap andthen heated in a 75° C. oil bath for 2h behind a blast shield then leftstanding overnight at room temperature. Reaction mixture was evaporatedon rotary evaporator. Residue was purified by normal phasechromatography to give 168C as a light yellow foam (0.315 g, 71.3%). MS(ESI) m/z: 434.3 (M+H)⁺378.3 (M+H-tBu)⁺.

168D.{3-Amino-4-[5-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-1,3,4-oxadiazol-2-yl]-phenyl}-carbamicacid methyl ester: 168C (0.315 g, 0.727 mmol) was dissolved in ethanol(4.5 mL) and iron powder (0.812 g, 14.54 mmol) was added. The mixturewas stirred at room temperature for I-2 min, then 0.1 M HCl (3.63 mL,0.363 mmol) was added, and the reaction was heated with stirring undernitrogen in a 50° C. oil bath for 1.5 h. Reaction was cooled to roomtemperature and filtered through a pad of CELITE,® and solids washedwith water, EtOH and EtOAc, then discarded. Filtrate was evaporated andremaining aqueous was diluted with NaHCO₃ to pH 8, then extracted 3×with EtOAc. Combined extracts were washed with saturated NaHCO₃ solutionand brine, dried over anhydrous Na₂SO₄ and filtered. Evaporation ofsolvents provided 168D as a crystalline solid. (0.257 g, 88%). MS (ESI)m/z: 404.3 (M+H)⁺348.3 (M+H-tBu)⁺.

168E.-[5-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1,3,4-oxadiazol-2-yl]-3-pent-4-enoylamino-phenyl}-carbamicacid methyl ester: 168D (0.275 g, 0.682 mmol) was dissolved in DCM (3.5mL) and pyridine (0.110 mL, 1.363 mmol) was added. The solution wascooled in an ice/salt water bath to ˜0° C., then 4-pentenoyl chloride(0.075 mL, 0.682 mmol) was added dropwise. The resulting mixture wasstirred at 0-5° C. for 1 h then allowed to warm to room temperature.After an additional 2h at room temperature, the reaction was dilutedwith EtOAc and washed with water, 1M HCl, sat'd NaHCO₃ and brine, thendried over anhydrous Na₂SO₄, filtered and evaporated. The crude productwas purified by normal phase chromatography to provide 168E as a whitesolid (0.276 g, 83%). MS (ESI) m/z: 486.3 (M+H)⁺430.3 (M+H-tBu)⁺

168F.((E)-(S)-15-tert-Butoxycarbonylamino-9-oxo-19-oxa-8,17,18-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16-hexaen-5-yl)-carbamicacid methyl ester: 168E (0.15 g, 0.309 mmol) was dissolved in DCE (500mL) in a 1 L flame-dried 3-neck flask fitted with a septum, refluxcondenser and argon inlet. The solution was degassed by bubbling Arthrough the solution for 30 min. Grubbs (II) (0.094 g, 0.111 mmol)catalyst was weighed out under argon and dissolved in 5 mL of degassedDCE and the dark red solution was added dropwise over 5-10 min to theabove solution. The resulting mixture was heated in a 75° C. oil bathfor ˜2h. Reaction was cooled to room temperature and solvent removed onrotary evaporator. Residue was taken back up in DCM and 0.375 gtris(hydroxymethyl)phosphine and 0.78 mL TEA were added. Mixture wasstirred for 10 min then water was added and vigorous stirring wascontinued for 15 min. Phases were separated and organic layer washedwith brine and dried over anhydrous Na₂SO₄. The crude product mixturewas purified by silica gel chromatography to provide 168F, the transisomer, as the major product (27 mg, 19.1%). MS (ESI) m/z: 458.3(M+H)⁺402.1 (M+H-tBu)⁺.

168G: Example 168 was prepared from 168F by removal of the Bocprotecting group and coupling with Intermediate 1, following theprocedures described for compounds 3C and 1G. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 10.04 (1 H, s) 9.91 (1 H, s) 9.84 (1 H, s) 9.04 (1 H, d, J=7.33Hz) 7.96 (1 H, d, J=1.77 Hz) 7.64-7.81 (3 H, m) 7.52 (1 H, s) 7.41 (1 H,dd, J=8.46, 1.64 Hz) 6.91 (1 H, d, J=16.00 Hz) 6.81 (1 H, d, J=16.00 Hz)5.43-5.63 (2 H, m) 5.11-5.22 (1 H, m) 3.70 (3 H, s) 2.57-2.70 (1 H, m)2.35-2.47 (3 H, m) 2.15-2.27 (2 H, m). MS (ESI) m/z: 590.2 (M+H)⁺.Analytical HPLC RT=5.80 min.

Unless otherwise stated, the compounds listed in the following tablescan be prepared by one skilled in the art of organic synthesis using theprocedures described in Examples I-168.

Examples I-1 to I-17 (Table I-1) were prepared by coupling 10H withappropriately substituted carboxylic acid derivatives (R—CO₂H) usingcoupling conditions described in step 15D. In the case of Examples I-4,I-12, and I-15, an additional Boc-deprotection step as described in step3C was required. Example I-18 was prepared by coupling 10H with anappropriately substituted carboxylic acid derivative (R—CO₂H) usingcoupling conditions described in step 15D followed by chlorination asdescribed in Example 7.

EXAMPLE I-20{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-17-fluoro-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, trifluoroacetic acid salt

I-20A.((S)-14-tert-Butoxycarbonylamino-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl)-carbamicacid methyl ester: To a brown solution of 10H (74.1 mg, 0.178 mmol) inTHF (4 mL) and water (2 mL) was added potassium carbonate (98 mg, 0.712mmol), followed by di-tert-butyl dicarbonate (0.062 mL, 0.267 mmol). Thereaction was stirred at rt for 12h. To the solution was added aq. NH₄Cl(10 mL) and 100 ul sat NH₄OH to quench the reaction. The reactionmixture was then extracted with EtOAc (30 mL×2). Organic solution wasdried over MgSO₄ and concentrated in vacuo, yielding oily mixture, whichwas purified on normal phase column chromatography (EtOAc/Hex) toprovide 40 mg (0.090 mmol, 50.7% yield) of I-20A as light brown oil. MS(ESI) m/z: 444.2 (M+1)⁺.

I-20B.((S)-14-Amino-17-fluoro-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl)-carbamicacid methyl ester: To a solution of I-20A (40 mg, 0.090 mmol) in DMF (3mL) was added sodium carbonate (12.43 mg, 0.117 mmol) and1-Fluoro-4-hydroxy-1,4diazoniabicyclo[2,2,2]octanebis(tetrafluoroborate) (50% in alumina)(62.9 mg, 0.090 mmol) in a portion, respectively and the resultingsolution was stirred for 2h at rt. The reaction mixture was diluted withMeOH and purified by reverse phase chromatography which gave both((S)-14-tert-Butoxycarbonylamino-17-fluoro-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl)-carbamicacid methyl ester and((S)-14-Amino-17-fluoro-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl)-carbamicacid methyl ester. The mixture was dissolved in 4N HCl dioxane (10 mL)and stirred overnight at 50° C. Concentration of the solution provided11 mg of I-20B (34%).

I-20C. Example I-20 was prepared following the procedures described instep 1G, by replacing 1F with 1-20B. ¹H NMR (400 MHz, CD₃OD) δ ppm9.40-9.59 (m, 1 H), 7.88-8.10 (m, 1 H), 7.62-7.85 (m, 1 H), 7.53-7.62(m, 1 H), 7.31-7.52 (m, 2 H), 7.07-7.22 (m, 1 H), 6.71-6.94 (m, 1 H),4.92-5.03 (m, 1 H), 2.36-2.50 (m, 1 H), 1.94-2.30 (m, 2 H), 1.75 (br.s., 2 H), 1.45 (br. s., 2 H), 0.99 (br. s., 1 H). MS(ESI) m/z: 594.2(M+H)⁺. Analytical HPLC: RT=6.79 min.

EXAMPLE I-22 MethylN-[(14S)-14-[(2E)-3-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]prop-2-enamido]-17-methyl-9-oxo-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2(7),3,5,15(18)-pentaen-5-yl]carbamate,trifluoroacetic acid

I-22A. tert-ButylN-[(14S)-17-bromo-5-[(methoxycarbonyl)amino]-9-oxo-16-{[2-(trimethylsilyl)ethoxy]methyl}-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2(7),3,5,15(18)-pentaen-14-yl]carbamate:To a cooled (<0° C.) solution of 10G (0.53 g, 0.924 mmol) in CHCl₃ (10mL) was added NBS (0.164 g, 0.924 mmol). The reaction was stirred underargon at 0° C. for 30 min. The solvent was removed. The crude productwas purified by normal phase chromatography to give I-22A (0.58 g, 96%)as a solid. MS (ESI) m/z: 652.2 (M+H)⁺ and 654.2 (M+2+H)⁺.

I-22B. tert-ButylN-[(14S)-5-[(methoxycarbonyl)amino]-17-methyl-9-oxo-16-{[2-(trimethylsilyl)ethoxy]methyl}-8,16,18-triazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2(7),3,5,15(18)-pentaen-14-yl]carbamate:To a solution of I-22A (0.53g, 0.812 mmol) in dioxane (15 mL) were addedNa₂CO₃ (0.430 g, 4.06 mmol), methylboronic acid (0.097 g, 1.624 mmol)and bis(tri-t-butylphosphine) palladium(0) (0.042 g, 0.081 mmol) at RT.The reaction mixture was purged with argon and then the reaction wasstirred under argon at 80° C. for 5 h. The reaction was cooled to RT.The reaction mixture was diluted with EtOAc, washed with sat NaHCO₃ andbrine. The organic phase was dried over sodium sulfate, filtered andconcentrated. In order to remove the des-Br by-product for betterpurification, it was converted back to bromoimidazole starting materialfollowing the procedure described in I-22A. The crude product waspurified by reverse phase chromatography to give I-22B (44 mg, 10%yield). MS (ESI) m/z: 588.4 (M+H)⁺.

I-22C. Example I-22 was prepared following the procedures described in10H, by replacing 10G with 1-22B; followed by step 1G. ¹H NMR (400 MHz,MeOD) δ ppm 9.57 (1 H, s, br), 9.50 (1 H, s), 7.96 (1 H, d, J=2.01 Hz),7.68 (1 H, dd, J=8.53, 2.26 Hz), 7.55-7.61 (2 H, m), 7.39-7.47 (2 H, m),7.14 (1 H, d, J=15.56 Hz), 6.73 (1 H, d, J=15.81 Hz), 5.03 (1 H, dd,J=10.16, 6.40 Hz), 3.76 (3 H, s), 2.37-2.48 (1 H, m), 2.31 (3 H, s),2.15-2.28 (1 H, m), 2.00-2.12 (1 H, m), 1.84-1.97 (1 H, m), 1.41-1.66 (3H, m), 0.96-1.18 (1 H, m). MS (ESI) m/z: 590.2 (M+H)⁺. Analytical HPLC:RT=4.38 min.

TABLE I-1 Examples I-1 to I-23

HPLC LCMS RT (min) Ex. # R R³ [M + H]⁺ (method) I-1

H 578.2 4.7 I-2

H 575.2 4.5 I-3

H 575.2 4.2 I-4

H 490.1 2.0 (B) I-5

H 575.2 5.0 I-6

H 574.2 6.1 I-7

H 551.1 5.0 4.8 (B) I-8

H 551.1 5.0 4.9 (B) I-9

H 549.2 6.2 I-10

H 549.2 5.6 I-11

H 498.2 4.0 I-12

H 513.2 6.2 (C) I-13

H 503.4 5.2 I-14

H 499.2 3.7 I-15

H 503.3 4.0 I-16

H 498.3 5.9 I-17

H 498.3 5.6 I-18

Cl 584.3 5.9 (B) I-19

Cl 608.2 8.0 I-20

F 594.2 6.8 I-21

F 556.2 4.9 I-22

Me 590.2 4.4 I-23

Me 608.2 5.2

Examples I-24 and I-25 (Table I-2) were prepared following theprocedures described in Example 116 and 118 by replacing2-methylbut-3-enoic acid with 3-methylbut-3-enoic acid.

TABLE I-2 Examples I-24 and I-25

HPLC LCMS RT (min) Ex. # R⁷ [M + H]⁺ (method) I-24 Me 590.3 5.0(homochiral) I-25 Me 590.3 5.0 (homochiral)

Examples I-26 to I-34 (Table I-3) were prepared following the generalprocedures described in Examples 116 and 118. Example I-26 and I-27 wereprepared by replacing benzyl 2-methylbut-3-enoate with methyl2-hydroxybut-3-enoate as described in Example 116C, followed by 116D,additional step of replacement of hydroxyl group with fluoride by DAST;followed by steps 116E; 116F; and 116I. Examples I-30 and I-31 wereprepared by replacing benzyl 2-methylbut-3-enoate with methyl2-methoxybut-3-enoate as described in Example 116C. Examples I-28, I-29and I-33 were prepared by replacing benzyl 2-methylbut-3-enoate withbenzyl 2-ethylbut-3-enoate or benzyl 2-isopropylbut-3-enoate asdescribed in Example 116C. Example I-32 was prepared by replacing benzyl2-methylbut-3-enoate with methyl 2-hydroxybut-3-enoate as described inExample 116C; followed by 116D; additional step of oxidation of thehydroxyl group to the ketone by Dess-Martin's reagent followed byfluorination with DAST; followed by steps 116E; 116F; and 116I. Examples135-138 were prepared by clorination of Examples 116G, 116H, I-33, andI-34 as described in Example 7. Examples I-39 to I-59 were prepared bycoupling macrocyclic cores with appropriately substituted carboxylicacid derivatives (R—CO₂H) using coupling conditions described in step15D. Example I-40, I-44, I-49 to I-51, I-54, I-55, I-57, I-59 wereprepared by coupling macrocyclic core with an appropriately substitutedcarboxylic acid derivative (R—CO₂H) using coupling conditions describedin step 15D followed by chlorination as described in Example 7.

TABLE I-3 Examples I-26 to I-59

HPLC Ex. LCMS RT (min) # R R⁷ R³ [M + H]⁺ (method) I-26

F (homochiral) H 593.9 3.7 (B) I-27

F (homochiral) H 593.9 3.6 (B) I-28

H 604.1 4.2 (B) I-29

H 604.1 4.2 (B) I-30

OMe (homochiral) H 606.2 5.3 I-31

OMe (homochiral) H 606.3 6.0 I-32

Bis-F H 612.1 3.8 (B) I-33

H 618.3 4.5 (B) I-34

H 618.3 4.5 (B) I-35

Cl 624.3 7.0 I-36

Cl 624.3 6.7 I-37

Cl 652.3 5.8 (B) I-38

Cl 652.3 5.8 (B) I-39

H 512.2 4.8 I-40

Cl 546.2 6.9 I-41

H 552.2 3.5 I-42

Me (diastereomer mixture) H 552.4 3.3 I-43

H 580.3 4.3 I-44

Me (diastereomer mixture) Cl 586.3 4.7 4.9 I-45

H 552.3 2.9 I-46

H 547.3 5.2 I-47

H 561.3 5.7 I-48

H 575.3 5.3 (B) I-49

Cl 581.3 7.5 I-50

Cl 595.3 7.7 I-51

Cl 599.2 7.8 I-52

H 602.3 6.4 I-53

H 588.2 5.9 I-54

Cl 622.3 7.9 I-55

Cl 636.3 8.4 I-56

H 552.3 3.8 (B) I-57

Cl 586.2 4.9 (B) I-58

H 566.4 4.6 I-59

Cl 585.4 7.7

Example I-60 was prepared following the procedures described in Example7, by replacing Example 6 with Example 154.

EXAMPLE I-61{(9S,14S)-17-Chloro-14-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-trifluoromethyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

I-61A and I-61AA.[(9S,14S)-17-Chloro-5-methoxycarbonylamino-9-trifluoromethyl-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester, 2TFA salt (I-61A) and[(9S,14S)-4,17-Dichloro-5-methoxycarbonylamino-9-trifluoromethyl-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester, 2TFA salt (I-61AA): To the solution of 154C(diastereomer A) (0.124 g, 0.145 mmol) in acetonitrile (1 mL)/chloroform(1.000 mL) was added NCS (0.029 g, 0.217 mmol) and DIPEA (0.076 mL,0.435 mmol). The reaction mixture was stirred at rt for 44 h. AnotherNCS (0.029 g, 0.217 mmol) added. After another 2.5 h, the reactionmixture was concentrated. Purification by reverse phase chromatographygave 0.024 g (18.6%) of I-61A as a yellow solid and 0.010 g (7.5%) ofI-61AA as a white solid. For I-61A: MS (ESI) m/z: 662.4 (M+H)⁺. ForI-61AA: MS (ESI) m/z: 696.3 (M+H)⁺.

I-61B.((9S,14S)-14-Amino-17-chloro-9-trifluoromethyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl)-carbamicacid methyl ester, 3TFA salt: To the solution of I-61A (0.032 g, 0.036mmol) in MeOH (0.5 mL) was added 5 N HCl (0.5 mL, 2.5 mmol) andmethoxylamine hydrochloride (25-30 wt. % in water, 0.055 mL, 0.180mmol). The reaction mixture was warmed to 75° C. for 1 h and then it wascooled to rt. Purification by reverse phase chromatography gave I-61B(0.02 g, 71.9%) as a white solid. MS (ESI) m/z: 432.2 (M+H)⁺.

I-61C. Example I-61 was prepared following the procedure described in15D, by replacing 15C with 1-61B. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.50 (s,1 H), 7.98 (d, J=2.5 Hz, 1 H), 7.66 (dd, J=8.5, 2.5 Hz, 1 H), 7.57 (d,J=8.5 Hz, 1 H), 7.30-7.34 (m, 2 H), 7.12 (d, J=15.7 Hz, 1 H), 7.07 (dd,J=8.3, 2.2 Hz, 1 H), 6.77 (d, J=15.7 Hz, 1 H), 5.14 (dd, J=10.6, 7.0 Hz,1 H), 3.74 (s, 3 H), 2.84-2.92 (m, 1 H), 2.13-2.22 (m, J=13.0, 13.0,7.1, 2.9 Hz, 1 H), 1.87-1.95 (m, 1 H), 1.63-1.81 (m, 2 H), 1.39-1.55 (m,3 H), 0.44-0.55 (m, 1 H). ¹⁹F NMR (471MHz, CD₃OD) δ −74.96, −77.49. MS(ESI) m/z: 664.3 (M+H)⁺. Analytical HPLC, RT=8.89 min.

Examples I-62 to I-64 were synthesized by coupling the amine 155A, withappropriately substituted carboxylic acid derivatives (R—CO₂H) usingcoupling conditions described in step 15D. In the case of Examples I-62and I-63 an additional Boc-deprotection step as described in step 3C wasrequired.

EXAMPLE I-67(9S,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acrylamino]-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid ethyl ester, 2 TFA salt

I-67A.2-{2-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-5-methoxycarbonylamino-phenylamino}-pent-4-enoicacid ethyl ester. To a clear yellowish-brown solution of 10C (4.50 g,8.46 mmol) and maleic acid (0.982 g, 8.46 mmol) in acetonitrile (33.9mL) was added a 50% solution ethyl 2-oxoacetate in toluene (2.52 mL,12.69 mmol) followed by allyltributyltin (4.72 mL, 15.23 mmol). Theresulting orange solution was stirred vigorously. After 18 h, thereaction was diluted with EtOAc and then the reaction was washed with1.0 N NaOH (75 mL×2), brine, dried over Na₂SO₄, filtered andconcentrated to give a viscous, orange oil. Purification by normal phasechromatography gave 3.96 g (76%) of I-67A as an orange foam. ¹H NMRindicated approximately a 1:1 mixture of diastereomers. MS (ESI) m/z:658.4 (M+H)⁺.

I-67B.(9R,14S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid ethyl ester (Diastereomer A), 2 TFA salt and I-67C.(9S,14S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid ethyl ester (Diastereomer B), 2 TFA salt.

Compounds I-67B (diastereomer A) and I-67C (diastereomer B) wereprepared following the procedures described in I-74C, by replacing I-74Bwith 1-67A; followed by step I-74D. The diastereomers were separated byreverse phase chromatography. MS (ESI) m/z: 632.5 (M+H)⁺.

I-67D. Example I-67 was prepared following the procedures described in154E, by replacing 154D with 1-67C (diastereomer B); followed by step15D. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.50 (s, 1 H), 9.39 (s, 1 H), 7.94(d, J=2.2 Hz, 1 H), 7.67 (dd, J=8.2, 2.2 Hz, 1 H), 7.55-7.60 (m, 1 H),7.51 (s, 1 H), 7.41 (s, 1 H), 7.28-7.35 (m, J=8.2 Hz, 1 H), 7.09-7.15(m, 2 H), 6.77 (d, J=15.4 Hz, 1 H), 5.15 (t, J=6.6 Hz, 1 H), 3.96-4.12(m, 2 H), 3.73 (s, 3 H), 3.09 (d, J=10.4 Hz, 1 H), 2.31-2.42 (m, 1 H),1.94-2.07 (m, 1 H), 1.56-1.79 (m, 2 H), 1.44-1.55 (m, 3 H), 1.14 (t,J=7.2 Hz, 3 H), 0.54-0.66 (m, 1 H). MS (ESI) m/z: 634.3 (M+H)⁺ and 636.2(M+2+H)⁺. Analytical HPLC (Method D): RT=4.9 min.

EXAMPLE I-68(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acrylamino]-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid ethyl ester, 2 TFA salt

I-68A.(9R,14S)-14-Amino-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid ethyl ester: Compound I-68A was prepared following the proceduredescribed in 154E, by replacing 154D with I-67B (diastereomer A). MS(ESI) m/z: 632.5 (M+H)⁺.

I-68B. Example I-68 was prepared following the procedures described in15D, by replacing 15C with I-68A. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.51 (s,1 H), 9.41 (s, 1 H), 7.98 (d, J=2.2 Hz, 1 H), 7.68 (dd, J=8.8, 2.2 Hz, 1H), 7.58 (d, J=8.2 Hz, 1 H), 7.56 (s, 1 H), 7.44 (s, 1 H), 7.35 (d,J=8.2 Hz, 1 H), 7.12-7.19 (m, 2 H), 6.77 (dd, J=15.4, 2.2 Hz, 1 H),5.20-5.30 (m, 1 H), 3.94-4.11 (m, 2 H), 3.74 (s, 3 H), 3.05 (d, J=10.4Hz, 1 H), 2.22-2.37 (m, 1 H), 1.96-2.07 (m, 1 H), 1.72-1.93 (m, 2 H),1.37-1.62 (m, 3 H), 1.12 (t, J=7.2 Hz, 3 H), 0.30-0.43 (m, 1 H). MS(ESI) m/z: 634.3 (M+H)⁺ and 636.2 (M+2+H)⁺. Analytical HPLC (Method D):RT=5.2 min.

Example I-69 was prepared by following the procedure described in 15D,by replacing 15C with I-68A and by replacing Intermediate 2 withIntermediate 3A.

TABLE I-4 Examples I-60 to I-69

HPLC LCMS RT (min) Ex. # R R⁷ R³ [M + H]⁺ (method) I-60

Cl 664.1 8.6 I-61

Cl 664.3 8.9 I-62

H 537.2 3.8 I-63

H 544.4 4.1 I-64

H 592.3 4.4 (D) I-65

F 648.2 8.8 I-66

F 610.2 7.1 I-67

H 634.3 4.9 (D) I-68

H 634.3 5.2 (D) I-69

H 652.3 5.7 (D)

Examples I-72 and I-73 were prepared according to the proceduresdescribed for Example I-67, by replacing ethyl 2-oxoacetate with theappropriately substituted aldehydes.

EXAMPLE I-74(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acrylamino]-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid methyl ester, 2 TFA salt

I-74A.(R)-2-(2-(2-((S)-1-(tert-Butoxycarbonylamino)but-3-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-5-(methoxycarbonylamino)phenylamino)pent-4-enoicacid: A thick-walled flask was charged with 10B (5 g, 8.39 mmol),copper(I) iodide (0.160 g, 0.839 mmol), potassium carbonate (2.90 g,20.99 mmol), (R)-2-aminopent-4-enoic acid (1.160 g, 10.07 mmol) and DMSO(16.8 mL). The flask was vacuumed and back-filled with argon three timesand then the flask was sealed with a teflon screw cap. The reaction wascapped, heated to 90° C. for 18 h, and then the reaction was cooled toRT. The reaction mixture was diluted with ethyl acetate and water andthe layers were separated. The aqueous layer was extracted with EtOAc(2×). The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated to give I-74A (5.5 g, 83%) as a yellow solid. MS(ESI) m/z: 630.4 (M+H)⁺. The material was carried onto the next stepwithout further purification.

I-74B.(R)-2-{2-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-5-methoxycarbonylamino-phenylamino}-pent-4-enoicacid methyl ester: To a solution of I-74A (5.5 g, 6.99 mmol) in DMF (100mL) was added K₂CO₃ (0.966 g, 6.99 mmol) and MeI (0.437 mL, 6.99 mmol).The reaction was stirred at RT for 24 h. The reaction was partitionedbetween EtOAc and water and the layers were separated. The aqueous layerwas extracted with EtOAc (1×). The combined organic layers were washedwith water, brine, dried over Na₂SO₄, filtered and concentrated.Purification by normal phase chromatography gave I-74B (2.36 g, 52.5%)as brown solid. MS (ESI) m/z: 644.5 (M+H)⁺.

I-74C.(9R,14S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaene-9-carboxylicacid methyl ester: A solution of I-74B (0.4 g, 0.621 mmol), Grubbs (II)(0.211 g, 0.249 mmol) in DCE (15.53 ml) was heated in a microwave at120° C. for 20 min. The reaction was cooled to RT. The same reaction wasrepeated eight more times. All nine reactions were combined, washed withsat. NaHCO₃, brine, dried over MgSO₄, filtered and concentrated.Purification by normal phase chromatography gave I-74C (1.03 g, 30%) asa brown solid. MS (ESI) m/z: 616.5 (M+H)⁺.

I-74D.(9R,14S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid methyl ester (diastereomer A), 2 TFA salt and I-74E.(9S,14S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid methyl ester (diastereomer B), 2 TFA salt. To the solution of I-74C(1.03 g, 1.673 mmol) in EtOAc (15 mL)/EtOH (5.00 mL) was added TFA(0.258 ml, 3.35 mmol) and 10% palladium on carbon (0.178 g, 0.167 mmol).Hydrogen was bubbled through the reaction mixture for 5 min. Thereaction was stirred under a hydrogen balloon for 4 days. The reactionwas filtered through a 0.45 μm GMF containing CELITE®. The solid wasrinsed with MeOH, and the filtrate was concentrated. The residue wasdissolved in EtOAc, washed with sat. NaHCO₃, brine, dried over Na₂SO₄,filtered and concentrated. Purification by normal phase chromatographygave I-74D (0.3 g, 29.0% yield) as a yellow solid. MS (ESI) m/z: 618.4(M+H)⁺. A mixture of I-74D and I-74E (0.55 g) was also obtained as ayellow solid. This mixture was purified by reverse phase chromatographyto give 0.325 g (23.0%) of I-74D (diastereomer A) as a white solid and0.23 g (16.3%) I-74E (diastereomer B) as a white solid. For I-74D: MS(ESI) m/z: 618.5 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ ppm 7.73 (s, 1 H),7.37 (d, J=1.9 Hz, 1 H), 7.30 (d, J=8.3 Hz, 1 H), 7.17 (dd, J=8.4, 2.1Hz, 1 H), 5.66 (d, J=10.5 Hz, 1 H), 5.53 (d, J=10.5 Hz, 1 H), 5.12 (t,J=9.1 Hz, 1 H), 3.65-3.77 (m, 5 H), 3.51 (s, 3 H), 3.03 (d, J=10.7 Hz, 1H), 2.07-2.16 (m, 2 H), 1.68-1.81 (m, 2 H), 1.31-1.55 (m, 12 H),0.90-1.04 (m, 2 H), 0.26-0.38 (m, 1 H), 0.01 (s, 9 H). [α]=-6.9 (c=1.23,MeOH).

For 1I-74E: MS (ESI) m/z: 618.4 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ ppm7.71 (s, 1 H), 7.39 (s, 1 H), 7.32 (d, J=8.3 Hz, 1 H), 7.13-7.17 (m, 1H), 5.85 (d, J=10.7 Hz, 1 H), 5.51 (d, J=11.0 Hz, 1 H), 5.13 (t, J=6.3Hz, 1 H), 3.70-3.76 (m, 5 H), 3.52-3.57 (m, 3 H), 3.09 (dd, J=9.4, 3.3Hz, 1 H), 2.27-2.36 (m, 1 H), 1.91-2.00 (m, 1 H), 1.70-1.79 (m, 1 H),1.31-1.69 (m, 13 H), 0.89-1.07 (m, 2 H), 0.43-0.54 (m, 1 H), 0.00 (s, 9H).

I-74F.(9R,14S)-14-Amino-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid methyl ester: Compound I-74F was prepared following the proceduredescribed in 154E, by replacing 154D with I-74D (diastereomer A). MS(ESI) m/z: 388.1 (M+H)⁺.

I-74G. Example I-74 was prepared following the procedure described in1G, by replacing 1F with I-74F. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.51 (s, 1H), 7.98 (d, J=2.2 Hz, 1 H), 7.68 (dd, J=8.8, 2.2 Hz, 1 H), 7.55-7.60(m, 2 H), 7.41 (d, J=2.2 Hz, 1 H), 7.35 (d, J=8.2 Hz, 1 H), 7.12-7.21(m, 2 H), 6.76 (d, J=15.4 Hz, 1 H), 5.25 (dd, J=11.0, 7.1 Hz, 1 H), 3.75(s, 3 H), 3.57 (s, 3 H), 3.07 (d, J=10.4 Hz, 1 H), 2.25-2.36 (m, 1 H),1.97-2.06 (m, 1 H), 1.72-1.90 (m, 2 H), 1.38-1.62 (m, 3 H), 0.30-0.43(m, 1 H). MS (ESI) m/z: 620.3 (M+H)⁺. Analytical HPLC: RT=5.66 min.

Example I-75 was prepared by following the procedure described inExample 7, by replacing Example 6 with Example I-74 and by running thereaction at rt in acetonitrile.

EXAMPLE I-76(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acrylamino]-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid, 2 TFA salt

I-76A.(9R,14S)-14-Amino-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid, 3 HCl salt: To a clear, pale yellow solution of I-74F (0.079 g,0.204 mmol) in MeOH (2.0 mL) was added 1N sodium hydroxide (0.408 ml,0.408 mmol). The solution was stirred vigorously at 55° C. for 1.5 h,cooled to RT, acidified with 1.0 N HCl (1 mL), and concentrated to giveI-76A (0.098 g, 0.187 mmol, 92% yield) as an off-white solid. MS (ESI)m/z: 374.1 (M+H)⁺. The material was carried onto the next step withoutfurther purification.

I-76B. Example I-76 was prepared following the procedure described in1G, by replacing 1F with 1-76A. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.51 (s, 1H), 7.98 (d, J=2.2 Hz, 1 H), 7.68 (dd, J=8.5, 2.2 Hz, 1 H), 7.58 (d,J=8.5 Hz, 1 H), 7.55 (s, 1 H), 7.40 (d, J=1.9 Hz, 1 H), 7.36 (d, J=8.5Hz, 1 H), 7.21 (dd, J=8.4, 2.1 Hz, 1 H), 7.16 (d, J=15.7 Hz, 1 H), 6.76(d, J=15.7 Hz, 1 H), 5.26 (dd, J=11.0, 7.2 Hz, 1 H), 3.74 (s, 3 H), 3.04(d, J=10.2 Hz, 1 H), 2.26-2.35 (m, J=13.3, 13.3, 7.2, 3.0 Hz, 1 H),1.98-2.06 (m, 1H), 1.73-1.94 (m, 2 H), 1.44-1.63 (m, 3 H), 0.35-0.46 (m,1 H). MS (ESI) m/z: 606.3 (M+H)⁺. Analytical HPLC: RT=5.47 min.

EXAMPLE I-77{(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-hydroxymethyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

I-77A.[(9R,14S)-14-tert-Butoxycarbonylamino-9-hydroxymethyl-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]-carbamicacid methyl ester: To a cooled (0° C.) solution of I-74D (0.22 g, 0.356mmol) in THF (5 mL) was added LAH (0.178 ml, 0.356 mmol) (2M in THF).The reaction was allowed to stir at 0° C. After 1 h, additional LAH(0.05 ml, 0.1 mmol) (2M in THF) was added. After an additional 1 h, thereaction was quenched with 1N HCl (aq, 1 mL). The reaction was dilutedwith EtOAc, washed with sat. NaHCO₃, brine, dried over Na₂SO₄, filteredand concentrated to give 0.217 g (103%) of I-77A as a yellow solid. MS(ESI) m/z: 590.5 (M+H)⁺. The material was carried onto the next stepwithout further purification.

I-77B. Example I-77 was prepared following the procedures described in154E, by replacing 154D with 1-77A; followed by step 15D. ¹H NMR (500MHz, CD₃OD) δ ppm 9.51 (s, 1 H), 7.99 (d, J=2.2 Hz, 1 H), 7.65-7.71 (m,2 H), 7.53-7.61 (m, 2 H), 7.49 (s, 1 H), 7.30 (dd, J=8.5, 2.2 Hz, 1 H),7.16 (d, J=15.7 Hz, 1 H), 6.77 (d, J=15.7 Hz, 1 H), 5.29 (dd, J=11.1,6.7 Hz, 1 H), 3.76 (s, 3 H), 3.52 (dd, J=11.6, 4.7 Hz, 1 H), 3.39-3.43(m, 1 H), 2.82-2.88 (m, 1 H), 2.16-2.26 (m, J=13.0, 13.0, 6.9, 3.4 Hz, 1H), 1.98-2.09 (m, 2 H), 1.86-1.94 (m, 1 H), 1.44-1.64 (m, 3 H),0.58-0.69 (m, 1 H). MS (ESI) m/z: 592.4 (M+H)⁺. Analytical HPLC: RT=5.62min.

EXAMPLE I-78{(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-dimethylcarbamoyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

I-78A.(9R,14S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid, 2 HCl salt: Compound I-78A was prepared by following the proceduredescribed in I-76A, by replacing I-74F with 1-74D. MS (ESI) m/z: 604.5(M+H)⁺. The material was carried onto the next step without furtherpurification.

I-78B.[(9R,14S)-9-Dimethylcarbamoyl-5-methoxycarbonylamino-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester: To the solution of I-78A (0.088 g, 0.074 mmol) inDMF (2 mL) was added EDC (0.028 g, 0.148 mmol), HOBT (0.023 g, 0.148mmol), dimethylamine, HCl (7.26 mg, 0.089 mmol) and TEA (0.041 mL, 0.297mmol). The reaction was stirred at RT. After 18h, the reaction wasdiluted with EtOAc and then washed with water, sat. NaHCO₃, brine, driedover Na₂SO₄, filtered and concentrated to give 0.047 g (100%) of I-78Bas a brown solid. MS (ESI) m/z: 631.5 (M+H)⁺. The material was carriedonto the next step without further purification.

I-78C. Example I-78 was prepared following the procedures described in154E, by replacing 154D with 1-78B; followed by step 1G. ¹H NMR (500MHz, CD₃OD) δ ppm 9.51 (s, 1 H), 7.98 (d, J=2.2 Hz, 1 H), 7.68 (dd,J=8.5, 2.2 Hz, 1 H), 7.56-7.63 (m, 2 H), 7.38 (d, J=8.5 Hz, 1 H), 7.29(dd, J=8.3, 1.9 Hz, 1 H), 7.24 (d, J=1.4 Hz, 1 H), 7.16 (d, J=15.7 Hz, 1H), 6.76 (d, J=15.7 Hz, 1 H), 5.27 (dd, J=11.3, 7.2 Hz, 1 H), 3.75 (s, 3H), 3.52 (d, J=10.7 Hz, 1 H), 2.80 (s, 3 H), 2.66 (s, 3 H), 2.26-2.36(m, 1 H), 1.87-2.06 (m, 2 H), 1.68-1.77 (m, 1 H), 1.56-1.66 (m, 1 H),1.43-1.54 (m, 1 H), 1.25-1.33 (m, 1 H), 0.32-0.43 (m, 1 H). MS (ESI)m/z: 633.5 (M+H)⁺. Analytical HPLC: RT=6.64 min.

EXAMPLE I-79{(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-methylcarbamoyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamic acid methyl ester, 2 TFA salt

Example I-79 was prepared following the procedure described in 15D, byreplacing Intermediate 2 with Example I-76 and by replacing 15C withmethanamine hydrochloride. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.51 (s, 1 H),7.98 (d, J=2.5 Hz, 1 H), 7.68 (dd, J=8.5, 2.2 Hz, 1 H), 7.58 (d, J=8.5Hz, 1 H), 7.53 (s, 1 H), 7.37-7.41 (m, 1 H), 7.25-7.29 (m, 2 H), 7.16(d, J=15.7 Hz, 1 H), 6.76 (d, J=15.7 Hz, 1 H), 5.26 (dd, J=11.1, 7.0 Hz,1 H), 3.74 (s, 3 H), 3.03 (dd, J=11.7, 1.5 Hz, 1 H), 2.57 (s, 3 H),2.24-2.33 (m, 1 H), 1.76-2.03 (m, 3 H), 1.41-1.58 (m, 2 H), 1.26-1.34(m, 1 H), 0.43-0.54 (m, 1 H). MS (ESI) m/z: 619.4 (M+H)⁺. AnalyticalHPLC: RT=4.78 min.

Examples I-80 and I-81 were prepared according to Example I-79 byreplacing methanamine hydrochloride with the appropriately substitutedamines. Examples I-82 to I-85 were prepared according to the proceduresdescribed for Examples I-74 to I-77. Examples I-86 to I-100 wereprepared according to the procedures described for Example I-67, byreplacing ethyl 2-oxoacetate with the appropriately substitutedaldehydes. For the preparation of compounds I-99 and I-100, the Boc andSEM deprotection was accomplished by replacing the 4M HCl in dioxane,cysteine at 75° C. with 5M aqueous H₂SO₄, cysteine in methanol at 75° C.

TABLE I-5 Examples I-70 to I-100

HPLC LCMS RT (min) Ex. # R⁷ R³ [M + H]⁺ (method) I-70

Me 644.4 6.3 I-71

Me 644.4 6.5 I-72

H 612.2 6.0 I-73

H 612.2 6.1 I-74

H 620.3 5.6 I-75

Cl 654.3 6.9 (D) I-76

H 606.3 4.6 I-77

H 592.4 5.6 I-78

H 633.3 5.5 I-79

H 619.4 4.8 I-80

H 659.4 6.5 (D) I-81

H 690.4 5.6 (D) I-82

H 620.2 5.6 I-83

Cl 654.2 7.5 I-84

H 606.3 5.1 I-85

H 592.3 4.3 I-86

H 642.3 4.6 I-87

  (diastereomer mixture) H 645.2 5.4 6.0 I-88

  (homochiral) H 656.3 5.4 I-89

  (homochiral) H 656.4 5.4 I-90

H 642.3 5.3 I-91

H 642.3 5.8 I-92

H 642.3 5.7 I-93

H 676.3 7.2 I-94

H 676.3 7.1 I-95

H 670.4 7.3 I-96

H 670.3 7.3 I-97 Me H 576.3 5.6 (diastereomer A) I-98 Me H 576.3 5.5(diastereomer B) I-99

  (diastereomer B) H 632.4 6.8 I-100

  (diastereomer A) H 632.3 9.3

EXAMPLE I-103(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-methoxycarbonylamino-9-trifluoromethyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid methyl ester

I-103A.2-{(E)-2-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-5-methoxycarbonylamino-phenylimino}-3,3,3-trifluoro-propionicacid methyl ester: To a solution of Example 10C (164 mg, 0.308 mmol),methyl 3,3,3-trifluoro-2-oxopropanoate (39 mg, 0.250 mmol) andtriethylamine (95 μl, 0.679 mmol) in 1 ml Toluene (Volume: 1028 μl) at0° C. under Ar was added titanium(IV) chloride (1M in DCM) (308 μl,0.308 mmol) dropwise. After addition, the ice bath was removed and thereaction was stirred at rt overnight. The reaction mixture was quenchedwith 1N NaOH (aq), partitioned between water and DCM, DCM layer driedover Na2SO₄, filtered off solid, concentrated to yield an orange oil.Purification by normal phase chromatography gave I-103A (95 mg, 46%) asan orange solid. MS (ESI) m/z: 670.4 (M+H)⁺.

I-103B.2-{2-[2-((S)-1-Amino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-5-methoxycarbonylamino-phenylamino}-2-trifluoromethyl-pent-4-enoicacid methyl ester: To a solution of I-103A (87 mg, 0.130 mmol) in CH₂Cl₂(Volume: 2 mL) was added allyltrimethylsilane (0.15 mL, 0.940 mmol). Thereaction was cooled down to −78° C. under Ar. Perchlorostannane (1M inDCM) (0.162 mL, 0.162 mmol) was added dropwise. After addition, the dryice acetone bath was removed and the reaction was warmed up to rt andstirred for 2 days. The reaction mixture was concentrated under vacuo toyield a crude solid product. Purification by reverse phasechromatography gave I-103B (35 mg, 44%) as a pale yellow solid. MS (ESI)m/z: 612.3 (M+H)⁺.

I-103C.2-{2-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-5-methoxycarbonylamino-phenylamino}-2-trifluoromethyl-pent-4-enoicacid methyl ester: To a solution of I-103B (35 mg, 0.057 mmol) inDioxane (Volume: 0.3 mL) was added di-tert-butyl dicarbonate (0.020 mL,0.086 mmol) and sodium hydroxide (1N in aq) (0.229 mL, 0.229 mmol). Thereaction was stirred at RT for 3 hrs, diluted with EtOAc, washed withwater and brine, dried over Na₂SO₄, filtered, and concentrated.Purification by normal phase chromatography gave I-103C (20 mg, 49%) asa pale yellow solid. MS (ESI) m/z: 712.5 (M+H)⁺.

I-103D. Example I-103 was prepared following the procedures described inI-74C by replacing I-74B with I-103C; followed by steps I-74D/I-74E;I-74F; I-74G. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.51 (s, 1 H), 7.98 (d,J=1.9 Hz, 1 H), 7.67 (d, J=2.2 Hz, 1 H), 7.54-7.61 (m, 1 H), 7.36 (s, 3H), 7.11-7.22 (m, 2 H), 6.71-6.81 (m, 1 H), 5.03-5.12 (m, 1 H), 3.73 (s,3 H), 3.67 (s, 3 H), 2.77-2.90 (m, 1 H), 1.99-2.17 (m, 2 H), 1.55-1.73(m, 2 H), 1.42-1.54 (m, 1 H), 0.93-1.07 (m, 1 H), 0.80-0.93 (m, 1 H). MS(ESI) m/z: 688.3 (M+H)⁺.

EXAMPLE I-106{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,10,15(18)-hexaen-5-yl}-carbamicacid methyl ester (90755-098)

I-106A.[(S)-5-Methoxycarbonylamino-9-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,10,15(18)-hexaen-14-yl]-carbamic acid tert-butyl ester: To asolution of mixture of 152A,152B and 152C (20 mg, 0.034 mmol) in 0.5 mlDCM at −78° C. under Ar was added methanesulfonyl chloride (5.83 mg,0.051 mmol) in 0.5 ml DCM dropwise. After 5 mins, triethylamine (10.29mg, 0.102 mmol) was added dropwise. The reaction bath was replaced withice-salt bath, gradually warmed up to 0° C. The reaction mixture waspartitioned between water and DCM. DCM layer washed with brine, driedover Na₂SO₄, filtered, and concentrated. Purification by reverse phasechromatography gave I-106A (5.3 mg, 27%) as a pale yellow solid. MS(ESI) m/z: 572.3 (M+H)⁺.

I-106B. Example I-106 was prepared following the procedures described in1F, by replacing 1D with 1-106A; followed by step 1G. ¹H NMR (500 MHz,CD₃OD) δ ppm 9.65-9.77 (m, 1 H), 9.51-9.56 (m, 1 H), 7.92-8.06 (m, 1 H),7.65-7.74 (m, 1 H), 7.56-7.64 (m, 2 H), 7.36-7.55 (m, 3 H), 7.18-7.28(m, 1 H), 6.61-6.76 (m, 1 H), 5.21-5.48 (m, 1 H), 4.40-4.64 (m, 1 H),3.74-3.80 (m, 3 H), 2.09-2.61 (m, 4 H). MS (ESI) m/z: 574.1 (M+H)⁺.Analytical HPLC: RT=3.91 min. (Method B).

EXAMPLE I-107{(E)-(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-17-fluoro-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,8,15(18)-hexaen-5-yl}-carbamicacid methyl ester, trifluoroacetic acid salt

I-107A.((E)-(S)-14-Amino-17-fluoro-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,8,15(18)-hexaen-5-yl)-carbamicacid methyl ester: To a yellow suspension of I-20B (18.67 mg, 0.043mmol) in THF (4 mL) was added borane-THF complex (1M) (0.430 mL, 0.430mmol) dropwise. It was sealed and heated at 60° C. for 1 hr and thencooled down to rt. To the solution was added MeOH, followed by 0.5 mlHCl (4M in dioxane). The reaction mixture was sealed and stored at rtovernight. The reaction mixture was then concentrated and purified byreverse phase chromatography to yield I-107A (4 mg, 25%). ¹H NMR (400MHz, CD₃OD) δ ppm 7.31 (d, J=8.34 Hz, 1 H) 7.16 (d, J=1.52 Hz, 1 H) 6.79(dd, J=8.46, 2.15 Hz, 1 H) 5.69 (dd, J=9.98, 3.41 Hz, 1 H) 4.69 (dd,J=11.37, 4.04 Hz, 1 H) 3.68-3.77 (m, 3 H) 2.11-2.32 (m, 1 H) 1.43-2.03(m, 6 H) 0.68-0.97 (m, 1 H). MS (ESI) m/z: 329.3 (M+H-NH₃)⁺.

I-107B. Example I-107 was prepared following the procedures described instep 1G, by replacing 1F with 1-107A. ¹H NMR (400 MHz, CD₃OD) δ □ppm9.52 (s, 1 H) 8.02 (d, J=2.26 Hz, 1 H) 7.66 (dd, J=8.53, 2.26 Hz, 1 H)7.50-7.59 (m, 1 H) 7.27 (d, J=8.03 Hz, 1 H) 7.13 (d, J=15.56 Hz, 2 H)6.73-6.90 (m, 2 H) 5.74 (br. s., 1 H) 5.18 (br. s., 1 H) 3.72 (s, 3 H)2.03-2.19 (m, 1 H) 1.55-1.97 (m, 5 H) 1.07-1.23 (m, 2 H). ¹⁹F NMR (376MHz, CD₃OD) δ ppm −139.71 (br. s., 1 F). MS(ESI) m/z: 578.3 (M+H)⁺.

EXAMPLE I-109{(10R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-10-methyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 2TFA salt

I-109A.((10R,14S)-14-Amino-10-methyl-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl)-carbamicacid methyl ester, 3 HCl salt: I-109A was prepared following theprocedure described in 1F, by replacing 1D with 116G.

I-109B.((10R,14S)-14-Amino-10-methyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl)-carbamicacid methyl ester, 3 TFA salt: To a yellow suspension of I-109A HCl salt(0.05 g, 0.116 mmol) in tetrahydrofuran (5 mL) was added Borane-THFcomplex (1M) (1.162 mL, 1.162 mmol), The reaction became clearcolorless. It was sealed and heated at 60° C. for 1 hr before coolingdown to rt. MeOH was added followed by addition of 1 ml HCl (4M indioxane). The reaction was sealed and heated at 60° C. overnight. Thereaction mixture was concentrated, dissolved in MeOH, filtered offsolid. Purification by reverse phase chromatography gave I-109B (5.3 mg,27%) as a pale yellow solid. MS (ESI) m/z: 344.3 (M+H)⁺.

I-109C. Example I-109 was prepared following the procedures described in1G, by replacing 1F with 1-109B. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.54 (s,1 H), 8.03 (d, J=2.5 Hz, 1 H), 7.71-7.76 (m, 1 H), 7.69 (dd, J=8.5, 2.2Hz, 1 H), 7.61 (d, J=8.5 Hz, 1 H), 7.43-7.49 (m, 1 H), 7.23-7.32 (m, 3H), 6.83 (d, J=15.7 Hz, 1 H), 5.31 (dd, J=11.3, 6.3 Hz, 1 H), 3.69 (s, 3H), 3.02-3.04 (m, 1 H), 2.99-3.02 (m, 1 H), 2.67-2.74 (m, 1 H),2.24-2.39 (m, 2 H), 2.05-2.15 (m, 1 H), 1.83-1.92 (m, 1 H), 1.54-1.65(m, 1 H), 1.40-1.51 (m, 1 H), 0.96 (d, J=7.2 Hz, 3 H). MS (ESI) m/z:576.2 (M+H)⁺. Analytical HPLC: RT=6.26 min.

EXAMPLE I-115{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-17-cyano-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

I-115A.[(S)-5-Methoxycarbonylamino-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester: I-115A was prepared from 10B following theprocedures described in step 10C, by replacing ammonium hydroxide withbut-3-enylamine and running the reaction at 90° C.; followed by steps2E/F; and 10G, by adding 2 equiv. of TFA and replacing themethanol/EtOAc mixture with EtOAc. MS (ESI) m/z: 560.5 (M+H)⁺.

I-115B.[(S)-5-Methoxycarbonylamino-8-(2,2,2-trifluoro-acetyl)-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester: A mixture of 115A (1.21 g, 2.162 mmol) and TEA(0.362 ml, 2.59 mmol) in EtOAc (10.81 ml) was cooled to 0° C. underArgon, and then TFAA (0.336 ml, 2.378 mmol) was added dropwise. After ˜2h at 0° C., the reaction mixture was diluted with EtOAc, washed withwater (2×) and brine, dried over MgSO₄, filtered, and concentrated.Residue was purified by flash column chromatography to yield I-115B asan off-white foam (1.14 g, 80%). MS (ESI) m/z: 656.5 (M+H)⁺.

I-115C.[(S)-17-Bromo-5-methoxycarbonylamino-8-(2,2,2-trifluoro-acetyl)-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester: To a cooled (<0° C.) solution of I-115B (1.14 g,1.738 mmol) in CHCl₃ (5.79 ml) was added NBS (0.325 g, 1.825 mmol). Thereaction was stirred under argon at 0° C. for 20 min. Reaction mixturewas evaporated and residue purified by flash column chromatography toyield I-115C as a light peach foam (1.3 g, 102%). MS (ESI) m/z: 734.5(M+H)⁺.

I-115D.[(S)-17-Cyano-5-methoxycarbonylamino-8-(2,2,2-trifluoro-acetyl)-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester: In a microwave vial, I-115C (0.1 g, 0.136 mmol)was added to a solution of zinc cyanide (0.016 g, 0.136 mmol) in DMF(2.72 ml). The mixture was evacuated/flushed with Ar three times, andthen tetrakis(triphenylphosphine)palladium(0) (7.86 mg, 6.81 μmol) wasadded. The vial was again evacuated/flushed with Ar three times, thencapped and heated at 120° C. in the microwave for 20 min. Another 0.05eq. of catalyst (7.86 mg) was added, the reaction vial was capped andevacuated/flushed with Ar three times, then heated at 120° C. in themicrowave for another 20 min. Reaction was evaporated to dryness and theresidue was purified by normal phase chromatography to yield I-115D as awhite foam, (0.088 g, 95%). MS (ESI) m/z: 681.5 (M+H)⁺.

I-115E. Example I-115 was prepared from I-115D following the proceduresdescribed in step I-61B and 1G to provide Example 115 as a white solid(0.0077 g, 19.8%). ¹H NMR (500 MHz, CD₃OD) δ ppm 9.91 (1 H, s) 9.55 (1H, d, J=1.10 Hz) 8.07 (1 H, br. s.) 8.02 (1 H, d, J=2.20 Hz) 7.97 (1 H,dd, J=8.25, 4.40 Hz) 7.69 (1 H, dd, J=8.80, 2.20 Hz) 7.59-7.63 (1 H, m)7.41 (1 H, dd, J=8.80, 2.20 Hz) 7.19-7.25 (1 H, m) 6.83 (1 H, dd,J=15.95, 2.20 Hz) 5.29 (1 H, dd, J=11.00, 6.05 Hz) 3.76 (3 H, s) 3.28 (1H, br. s.) 2.99-3.07 (1 H, m) 2.14-2.23 (1 H, m) 2.04-2.14 (2 H, m)1.85-1.93 (1 H, m) 1.69 (2 H, t, J=12.92 Hz) 1.42 (1 H, t, J=9.62 Hz)0.88 (1 H, q, J=11.18 Hz). MS (ESI) m/z: 587.3 (M+H)⁺. Analytical HPLC:RT=5.83 min.

EXAMPLE I-116{(S)-17-Bromo-14-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA

Example I-116 was prepared from I-115C following the proceduresdescribed in step I-61B and 1G, as a white solid (0.046 g, 78%). ¹H NMR(500 MHz, CD₃OD) δ ppm 9.75 (1 H, s) 9.55 (1 H, s) 8.88 (1 H, d, J=4.40Hz) 8.02 (1 H, d, J=2.20 Hz) 7.98 (1 H, d, J=8.80 Hz) 7.96 (1 H, br. s.)7.70 (1 H, dd, J=8.80, 2.20 Hz) 7.60-7.64 (1 H, m) 7.33 (1 H, dd,J=8.80, 2.20 Hz) 7.24 (1 H, d, J=15.40 Hz) 6.81 (1 H, d, J=15.40 Hz)5.22 (1 H, dd, J=11.00, 6.60 Hz) 3.73 (3 H, s) 3.19-3.25 (1 H, m) 2.95(1 H, t, J=12.10 Hz) 2.10-2.19 (1H, m) 1.97-2.09 (2H, m) 1.82-1.91 (1H,m) 1.68 (2H, t, J=12.37 Hz) 1.37 (1 H, br. s.) 0.72-0.84 (1 H, m). MS(ESI) m/z: 640.3 (M+H)⁺. Analytical HPLC: RT=6.34 min.

EXAMPLE I-118(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-17-carboxylicacid ethyl ester, 2 TFA

I-118A.(S)-14-Amino-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-17-carboxylicacid ethyl ester, 3TFA: I-115D (0.086 g, 0.126 mmol) was dissolved inEtOH (0.5 ml), and then concentrated H₂SO₄ (10.10 μl, 0.189 mmol) wasadded at room temperature. The reaction was refluxed at 90° C. under Arovernight. Additional EtOH (2 mL) and conc. H₂SO₄ (0.2 mL) were added,and the reaction was heated at 90° C. for an additional 18 h then cooledto room temperature and poured into cold water. The aqueous layer wasadjusted to pH˜10 with 1N NaOH and extracted 3× with EtOAc; the combinedorganic layers were washed with brine, dried over MgSO₄, filtered, andevaporated. The residue was purified by reverse phase HPLC to provideI-118A (0.019 g, 20.2%). MS (ESI) m/z: 402.3 (M+H)⁺.

I-118B. Example I-118 was obtained as a light yellow solid from I-118Afollowing the procedure described in Step 1G (0.014 g, 58.5%). ¹H NMR(500 MHz, CD₃OD) δ ppm 9.78 (1 H, s) 9.52 (1 H, s) 8.32 (1 H, dd,J=8.67, 1.51 Hz) 8.03 (1 H, d, J=2.20 Hz) 8.01 (1 H, d, J=2.20 Hz) 7.68(1 H, dd, J=8.39, 2.34 Hz) 7.60 (1 H, d, J=8.53 Hz) 7.32 (1 H, d, J=8.80Hz) 7.19 (1 H, d, J=15.41 Hz) 6.80 (1 H, d, J=15.41 Hz) 5.32 (1 H, dd,J=10.04, 6.46 Hz) 4.32-4.41 (2 H, m) 3.77 (3 H, s) 3.21 (1 H, ddd,J=12.52, 4.13, 3.99 Hz) 2.93-3.03 (1 H, m) 2.09-2.19 (1 H, m) 1.81-2.05(3 H, m) 1.68 (2 H, t, J=12.24 Hz) 1.37 (3 H, t, J=7.15 Hz) 1.30 (1 H,d, J=6.88 Hz) 0.69-0.81 (1 H, m). MS (ESI) m/z: 634.4 (M+H)⁺. AnalyticalHPLC: RT=6.46 min.

EXAMPLE I-119(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-methoxycarbonylamino-9,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid methyl ester, 1TFA salt

I-119A.{4-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-formyl-phenyl}-carbamicacid methyl ester: To a solution of 10B (351 mg, 0.589 mmol) in THF (3ml) at −78° C. was added methyllithium (0.786 ml, 1.179 mmol). Thereaction was stirred at −78° C. for 30 min, then butyllithium (0.552 ml,0.884 mmol) in hexanes was added dropwise. After 30 mins, DMF (0.055 ml,0.707 mmol) was added to the reaction mixture. The reaction was stirredat −78° C. before it was quenched with conc. NH₄Cl (aq), extracted withether (2×), combined ether layers was washed with brine, dried overMgSO₄, filtered, and concentrated to yield a yellow oil. Purification bynormal phase chromatography gave I-119A as a pale yellow foam (187 mg,58%). MS (ESI) m/z: 545.2 (M+H)⁺.

I-119B.{3-Allylaminomethyl-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: To a solution of I-119A (187 mg, 0.343 mmol) in DCM(3.433 ml) was added prop-2-en-1-amine (19.60 mg, 0.343 mmol) and a dropof AcOH. The reaction was stirred at rt for 30 min, sodiumtriacetoxyborohydride (109 mg, 0.515 mmol) was added. After 3 hrs, thereaction was diluted with DCM, washed with sat. Na₂CO₃, brine, driedover MgSO₄. Filtered and concentrated. Purification by normal phasechromatography gave I-119B as a white foam (145 mg, 72%). MS (ESI) m/z:586.5 (M+H)⁺.

I-119C.[(S)-5-Methoxycarbonylamino-16-(2-trimethylsilanyl-ethoxymethyl)-9,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamic acid tert-butyl ester: I-119Cwas prepared following the procedures described in 2E/2F, by replacing2D with 1-119B; followed by 2G. MS (ESI) m/z: 560.4 (M+H)⁺.

I-119D.(S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-16-(2-trimethylsilanyl-ethoxymethyl)-9,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid methyl ester: To a solution of I-119C (14 mg, 0.021 mmol) in CH₂Cl₂(Volume: 1 mL) was added methyl chloroformate (1.967 μl, 0.025 mmol) in0.4 ml DCM, followed by TEA (0.014 mL, 0.099 mmol). The reaction wasstirred at rt. for 30 min. The reaction mixture was concentrated,redissolved in EtOAc, washed with water and brine, dried over Na₂SO₄,filtered off solid, concentrated. Purification by normal phasechromatography gave I-119D as a white solid (7 mg, 55%). MS (ESI) m/z:618.5 (M+H)⁺.

I-119E. Example I-119 was prepared following the procedures described in1F, by replacing 1D with 1-119D; followed by 1G. ¹H NMR (500 MHz, CD₃OD)δ ppm 9.51-9.53 (m, 1 H), 7.98 (d, J=2.5 Hz, 1 H), 7.67-7.72 (m, 2 H),7.55-7.61 (m, 2 H), 7.49 (s, 1 H), 7.40 (d, J=8.2 Hz, 1 H), 7.18 (d,J=15.7 Hz, 1 H), 6.76 (d, J=15.7 Hz, 1 H), 4.92-4.98 (m, 1 H), 4.31-4.52(m, 1 H), 3.77 (s, 3 H), 3.62-3.65 (m, 2 H), 3.61 (s, 3 H), 3.04-3.18(m, 1 H), 2.98-3.01 (m, 1 H), 2.13-2.28 (m, 1 H), 1.77-1.92 (m, 1 H),1.51-1.69 (m, 1 H), 1.20-1.43 (m, 2 H). MS (ESI) m/z: 620.3 (M+H)⁺.Analytical HPLC: RT=4.56 min. (Method B).

TABLE I-6 Examples I-101 to I-121

HPLC Ex. LCMS RT (min) # L—Y R³ [M + H]⁺ (method) I-101

H 634.3 4.5 (B) I-102

H 634.3 5.0 (B) I-103

H 688.3 5.1 (B) I-104

H 688.3 5.8 (B) I-105

H 640.2 5.4 I-106

H 573.9 3.9 (B) I-107

F 578.3 8.6 I-108

H 620.2 5.5 I-109

H 576.3 4.8 (B) I-110

H 576.2 6.2 I-111

H 576.3 6.3 I-112

Cl 610.3 5.7 (B) I-113

H 598.2 4.9 (B) I-114

H 619.3 5.0 I-115

CN 587.3 5.8 I-116

Br 640.3 6.3 I-117

Me 576.4 5.8 I-118

CO₂Et 634.4 6.5 I-119

H 620.3 4.6 (B) I-120

H 576.4 7.2 I-121

H 648.5 7.6

EXAMPLE I-123{(S)-17-Chloro-14-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid 2-methoxy-ethyl ester, 2 TFA

I-123A.{(S)-1-[4-(4-Amino-2-bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-but-3-enyl}-carbamicacid tert-butyl ester: To a stirred solution of 10B (1.5 g, 2.52 mmol)dissolved in MeOH (36 mL) was added 1N NaOH (50.4 mL, 50.4 mmol)dropwise at room temperature. The reaction was stirred at 85° C. under areflux condenser overnight. Solvent was removed under reduced pressureand the residue was partitioned between EtOAc/water. Aqueous layer wasextracted with EtOAc 3×, combined organic phases were washed with brine,dried with sodium sulfate, filtered and evaporated to yield the crudeproduct, I-123A (1.42 g, 105%), as a yellow solid. MS (ESI) m/z: =537.2(M+H)⁺.

I-123B.{3-Bromo-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid 2-methoxy-ethyl ester: I-123A (1.42 g, 2.64 mmol) was dissolved inDCM (26.4 ml). Pyridine (0.855 ml, 10.57 mmol) was added followed bydropwise addition of 2-methoxyethyl carbonochloridate at 0° C. Thereaction was allowed to warm to RT and stirred ON. Another 2 equiv. of2-methoxyethyl carbonochloridate (0.439 g, 3.17 mmol) was added andstirring was continued at RT for 2 hours. The reaction was quenched withsat.'d sodium bicarbonate and extracted with EtOAc 3×. Combined organicphases were washed with brine, dried over sodium sulfate, filtered andconcentrated. Crude product was purified by silica gel chromatography toprovide I-123B (1.23 g, 72.8%) as a yellow, oily solid. MS (ESI) m/z:=639.3/641.3 (M+H)⁺.

I-123C.{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid 2-methoxy-ethyl ester: I-123C was prepared from I-123B using theprocedures described for 115A, 61B and 1G. Crude product was usedwithout purification in the next step. MS (ESI) m/z: =606.4 (M+H)⁺.

I-123D. Example I-123: 1-123C (0.085 g, 0.140 mmol) was dissolved inacetonitrile (1 ml)/chloroform (1 ml) and TFA (0.086 ml, 1.122 mmol) wasadded followed by NCS (0.022 g, 0.168 mmol), and the mixture was stirredat 65° C. under Ar for 1.75 h. Reaction was diluted with water andextracted with EtOAc 2×. Combined organics were washed with brine, driedover sodium sulfate, filtered and concentrated. The crude product waspurified by reverse phase chromatography to provide Example I-123 (0.056g, 44.6%) as a yellow solid. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.79 (1 H,br. s.), 9.54 (1 H, s), 8.90 (1 H, d, J=5.50 Hz), 8.02 (1 H, d, J=2.20Hz), 7.93 (1 H, br. s.), 7.86 (1 H, d, J=8.80 Hz), 7.67-7.72 (1 H, m),7.58-7.64 (1 H, m), 7.32 (1 H, dd, J=8.80, 2.20 Hz), 7.18-7.28 (1 H, m),6.81 (1 H, d, J=15.95 Hz), 5.20 (1 H, dd, J=11.27, 6.32 Hz), 4.17-4.29(2 H, m), 3.61 (2 H, t, J=4.67 Hz), 3.37 (3 H, s), 3.18-3.26 (1 H, m),2.90-3.02 (1 H, m), 1.94-2.21 (3 H, m), 1.78-1.91 (1 H, m), 1.62-1.74 (2H, m), 1.30-1.45 (1 H, m), 0.72-0.91 (1 H, m). MS (ESI) m/z: =640.3(M+H)⁺. Analytical HPLC: RT=5.9 min.

TABLE I-7 Examples I-122 to I-127

HPLC Ex. LCMS RT # R R³ [M + H]⁺ (min) I-122

H 606.3 6.2 I-123

Cl 640.3 5.9 I-124

H 632.4 5.9 I-125

H 620.4 5.9 I-126

H 634.4 6.3 I-127

H 592.4 5.2

EXAMPLE I-134 MethylN-[(14S)-14-[(2E)-3-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]prop-2-enamido]-9-oxo-18-oxa-8,16-diazatricyclo[13.2.1.0^(2,7)]octadeca-1(17),2(7),3,5,15-pentaen-5-yl]carbamate,trifluoroacetic acid salt

I-134A. Methyl 4-(2-aminoacetyl)-3-bromophenylcarbamate: To a solutionof Intermediate 8 (3.0 g, 8.55 mmol) in acetonitrile (40 mL) was addedsodium diformylamide (0.975 g, 10.26 mmol). The suspension was stirredunder argon at RT for 5 hrs. The mixture was filtered and the solid waswashed with warm MeCN. The filtrate was concentrated to give a tansolid. Next, aq. 4 N HCl (25 mL) was added and the resulting suspensionwas warmed to reflux. After 2 h, the clear reaction was cooled to RT andthe solution was concentrated to give 2.45 g (100%) of I-134A as a lighttan solid. MS (ESI) m/z: 287.0 (M+H)⁺ and 288.9 (M+2+H)⁺.

I-134B. tert-ButylN-[(1S)-1-[(2-{2-bromo-4-[(methoxycarbonyl)amino]phenyl}-2-oxoethyl)carbamoyl]but-3-en-1-yl]carbamate:To a solution of (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (515mg, 2.393 mmol) in DMF (15 mL) was added HOBt (476 mg, 3.11 mmol) andEDC (596 mg, 3.11 mmol). After 5 min, a solution of I-134A (774 mg,2.393 mmol) and DIEA (0.418 ml, 2.393 mmol) in DMF (5 mL) was added. Thereaction was stirred under argon at RT for 2 h. The reaction mixture wasdiluted with EtOAc, washed with 1M HCl, sat NaHCO₃ and brine. Theorganic phase was dried over sodium sulfate, filtered and concentrated.Purification by normal phase chromatography gave 1.05 g (91%) of I-134Bas a tan solid. MS (ESI) m/z: 484.0 (M+H)⁺ and 485.9 (M+2+H)⁺.

I-134C. tert-ButylN-[(1S)-1-(5-{2-bromo-4-[(methoxycarbonyl)amino]phenyl}-1,3-oxazol-2-yl)but-3-en-1-yl]carbamate:A solution of I-134B (900 mg, 1.858 mmol) and Burgess reagent (1771 mg,7.43 mmol) in THF(10 mL) was microwaved at 120° C. for 12 min. Thereaction mixture was diluted with EtOAc, washed with H₂O and brine. Theorganic phase was dried over sodium sulfate, filtered and concentrated.The crude product was purified by normal phase chromatography which gave398 mg (46%) of I-134C as a solid. MS (ESI) m/z: 466.0 (M+H)⁺ and 468.0(M+2+H)⁺.

I-134D. Example I-134 was prepared following the procedures described in10C (alternative), by replacing 10B with 1-134C; followed by steps 10D;2E/2F, by replacing DCM with DCE and running the reaction at 70° C.; 2G;3C; and 1G. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.72 (1 H, s), 9.70 (1 H,s), 9.59 (1 H, s), 8.64 (1 H, d, J=7.53 Hz), 7.78 (1 H, d, J=2.01 Hz),7.60 (1 H, dd, J=8.53, 2.26 Hz), 7.57 (1 H, d, J=8.53 Hz), 7.38 (1 H, d,J=8.53 Hz), 7.27 (1 H, dd, J=8.66, 1.88 Hz), 7.16 (1 H, d, J=1.76 Hz),7.13 (1 H, s), 6.75 (1 H, d, J=15.56 Hz), 6.68 (1 H, d, J=15.56 Hz),4.91-5.02 (1 H, m), 3.53 (3 H, s), 1.84-1.94 (1 H, m), 1.73-1.84 (1 H,m), 1.60-1.73 (2 H, m), 1.40-1.54 (1 H, m), 1.12-1.25 (1 H, m),0.73-0.91 (1 H, m). MS (ESI) m/z: 577.2 (M+H)⁺. Analytical HPLC: RT=6.39min.

EXAMPLE I-136

I-136A. 5-Bromo-6-nitro-1H-indazole: A solution of sodium nitrite (2.189g, 31.7 mmol) in water (6.29 mL) was added dropwise to a solution of4-bromo-2-methyl-5-nitroaniline prepared according to J. Org. Chem.,44:4609 (1979) (7.33 g, 31.7 mmol) in glacial acetic acid (793 ml), andthe reaction mixture was stirred under argon at room temperatureovernight. The mixture was concentrated to give an oily residue. Waterwas added to precipitate the crude product which was collected viafiltration and washed with water, then dried in vacuo to yield an orangesolid. The solid was dried by lyophilization to yield I-136A (6.77 g,88%). (M+H)⁺ MS (ESI) m/z: 242.1 (M+H)⁺.

I-136B. 5-(1-Ethoxyvinyl)-6-nitro-1H-indazole: A solution of I-136A(7.65 g, 31.6 mmol), tributyl(1-ethoxyvinyl)stannane (12.81 ml, 37.9mmol), and (Ph₃P)₂PdCl₂ (1.109 g, 1.580 mmol) in toluene (63.2 ml) washeated at 115° C. under Ar. The reaction was cooled to room temperatureand filtered. The filtrate was concentrated and dried under vacuum toyield a dark brown oil, which was dissolved in DCM and absorbed on a drypad of silica gel. The pad was washed sequentially with Hex and EtOAc.The EtOAc fraction was condensed to a dark brown oil, which was furtherpurified by normal phase chromatography to provide an ˜3:1 mixture of SMto product. This mixture was dissolved in dioxane, andtributyl(1-ethoxyvinyl)stannane (3.46 ml, 10.23 mmol), CuI (0.162 g,0.852 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.492 g,0.426 mmol) were added. The mixture was degassed and then heated at 110°C. under Ar for 3 hrs, then allowed to sit at rt overnight. The reactionmixture was filtered and solids washed with EtOAc. Filtrate was strippedto a brown oil which was purified by flash chromatography to yieldI-136B as an orange oil, (1.93 g, 61.1%). MS (ESI) m/z: 234.1 (M+H)⁺.

I-136C. 2-Bromo-1-(6-nitro-1H-indazol-5-yl)ethanone: To a soln of I-136B(1.39 g, 5.96 mmol) in THF (8.83 ml) and water (3.09 ml) was added NBS(1.061 g, 5.96 mmol). The reaction was stirred at rt for ˜45 min, thenpartitioned between EtOAc/brine. The brine layer was re-extracted withEtOAc, and the combined organic layer was dried over MgSO₄, filtered,concentrated, and dried under vacuum to yield an 2.01 g of an orangesolid which was combined with 0.698 g from a second prep and dissolvedin a small amount of methylene chloride. The insoluble tan solid wasfiltered off to provide 0.381 g (16.6%) of product. The filtrate waspurified by normal phase chromatography to provide and additional 0.783of I-136C (34%). MS (ESI) m/z: 284.1 (M+H)⁺.

Example I-136D. The title compound was prepared from I-136C followingthe procedures described for 2A; 1B; 10B; 122C; 10D; 2E; 2G; 10H; and1G. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 14.27 (1 H, br. s.) 13.26 (1 H, s)9.86 (1 H, s) 9.63 (1 H, br. s.) 8.89 (1 H, br. s.) 8.17 (1 H, s) 7.99(1 H, s) 7.92 (1 H, d, J=2.20 Hz) 7.72-7.80 (2 H, m) 7.64 (1 H, br. s.)7.43 (1 H, br. s.) 6.91-6.97 (1 H, m) 6.80-6.85 (1 H, m) 5.04 (1 H, dt,J=9.83, 4.85 Hz) 2.34-2.40 (1 H, m) 2.10 (1 H, br. s.) 2.00 (1 H, br.s.) 1.82 (1 H, br. s.) 1.63 (1 H, br. s.) 1.39 (1 H, br. s.) 1.28 (1 H,br. s.) 0.89 (1 H, br. s.). MS (ESI) m/z: 543.3 (M+H)⁺. Analytical HPLC:RT=4.8 min.

EXAMPLE I-140

I-140A. 3-Amino-N-methoxy-N,4-dimethylbenzamide: 3-amino-4-methylbenzoicacid (5.0 g, 33.1 mmol) was dissolved in DMF (165 ml) and TEA (23.05 ml,165 mmol), EDC (7.93 g, 41.3 mmol), HOBT (6.33 g, 41.3 mmol), andN,O-dimethylhydroxylamine hydrochloride (8.07 g, 83 mmol) were added.The reaction was stirred under Ar at room temperature overnight. Themixture was diluted with EtOAc and washed 3× with water. The combinedaq. washes were re-extracted with EtOAc. The organic layers werecombined and washed with brine, then dried over MgSO₄, filtered andconcentrated. The resulting orange residue was purified by normal phasechromatography to yield the product as a colorless oil (2.87 g, 44.7%).MS (ESI) m/z: 195.1 m/z (M+H)⁺.

I-140B. 5-Amino-2-bromo-N-methoxy-N,4-dimethylbenzamide: NBS (2.52 g,14.16 mmol) was added to a solution of I-140A (2.75 g, 14.16 mmol) inDMF (28.3 ml), and the mixture was stirred overnight at roomtemperature. The reaction mixture was diluted with H₂O and extracted 3×with EtOAc. The organic extracts were combined and washed with brine,then dried over MgSO₄, filtered, and evaporated. Residue was dissolvedin a small amount of methylene chloride and the precipitate was filteredoff to provide product as a white solid (1.53 g, 39.6%). The filtratewas purified by normal phase chromatography to provide additionalproduct (1.13g, 29.2%). MS (ESI) m/z: 273.1 m/z (M+H)⁺.

I-140C. 5-Bromo-N-methoxy-N-methyl-1H-indazole-6-carboxamide: Thiscompound was prepared from I-140B (2.66 g, 9.74 mmol) following theprocedure described for step I-136A The product was isolated as a yellowsolid (2.55g, 92%). MS (ESI) m/z: 284.1 m/z (M+H)⁺.

I-140D. tert-Butyl5-bromo-6-(methoxy(methyl)carbamoyl)-1H-indazole-1-carboxylate: Asolution of I-140C (2.55 g, 8.98 mmol), (Boc)O₂ (4.79 ml, 20.64 mmol),TEA (5.00 ml, 35.9 mmol), and DMAP (0.658 g, 5.39 mmol) in THF (44.9 ml)was stirred under Ar at rt overnight. The reaction mixture wasconcentrated to remove THF and partitioned between EtOAc and saturatedaq. NH₄Cl solution. Layers were separated, and aqueous phasere-extracted with EtOAc. The org layers were combined and washed withbrine, then dried over MgSO₄, filtered, and evaporated. Crude productwas purified by normal phase chromatography to provide I-140D as a lightyellow foam (3.23 g, 94%). MS (ESI) m/z: 384.1 m/z (M+H)⁺

I-140E. 1-(5-Bromo-1H-indazol-6-yl)ethanone: To a solution of I-140D(3.1 g, 8.07 mmol) in THF (81 ml) in a 3-neck rbf at 0° C. was added 4eq. of methylmagnesium bromide (1.4 M in THF:Toluene, 23.05 ml, 32.3mmol) dropwise over 20 min. The resulting yellow soln was stirred underargon at 0° C. After ˜1.5 hrs from the start of the addition anadditional 3 eq of methylmagnesium bromide (1.4 M in THF:Toluene, 17.29ml, 24.20 mmol) was added dropwise to the cold soln. The mixture wasthen stirred under Ar overnight allowing the reaction to graduallyassume room temperature. Another 1.5 eq. of methylmagnesium bromide (1.4M in THF:Toluene. 8.64 ml, 12.10 mmol) was then added dropwise over ˜10min at rt, and the reaction was stirred at rt under Ar for an additional3 h prior to workup. The reaction was quenched at 0° C. with MeOHfollowed by a little water, then diluted with EtOAc. The suspension wasadjusted to pH5 to dissolve the solids and then evaporated to removeTHF. Additional EtOAc was added, and organics were washed with diluteaq. acid (pH ˜5), sat. NaHCO₃, and brine, then dried over MgSO₄,filtered and concentrated. The crude product was purified by normalphase chromatography to provide I-140E as a white solid (1.45 g, 75%).MS (ESI) m/z: 239.1 m/z (M+H)⁺

I-140F. 2-Bromo-1-(5-bromo-1H-indazol-6-yl)ethanone: I-140E (1.45 g,6.07 mmol) was taken up in THF (30.3 ml), and pyridinium tribromide(1.959 g, 6.13 mmol) was added. The mixture was stirred under Ar at rtfor 15 min then at 40° C. for 20 min. The reaction was evaporated andthe resulting pale yellow solid was partitioned between EtOAc/water. Theorganic layer was washed with water and brine, dried over MgSO₄,filtered, and evaporated. The residue was purified by flashchromatography to provide the desired monobromo product, I-140F (1.14 g,59%). MS (ESI) m/z: 319.0 m/z (M+H)⁺

Example I-140. The title compound was prepared from I-140F following theprocedures described for steps 2A; 1B; 10B; 10C by substituting3-butenamine for ammonium hydroxide; 2E/F; 154C/D; I-61B; and 1G. ¹H NMR(500 MHz, CD₃OD) δ ppm 9.56 (1 H, s) 8.18 (1 H, d, J=1.10 Hz) 8.02 (1 H,d, J=2.75 Hz) 7.79 (1 H, s) 7.69 (1 H, dd, J=8.80, 2.20 Hz) 7.62 (1 H,d, J=8.25 Hz) 7.60 (1 H, br. s.) 7.51 (1 H, s) 7.25 (1 H, d, J=15.40 Hz)6.85 (1 H, d, J=15.95 Hz) 5.28 (1 H, dd, J=11.00, 6.60 Hz) 3.20 (1 H, d,J=12.65 Hz) 2.94 (1 H, t, J=12.37 Hz) 2.13-2.22 (1 H, m) 2.09 (2 H, t,J=12.65 Hz) 1.86-1.94 (1 H, m) 1.61-1.79 (2 H, m) 1.30-1.40 (1 H, m)0.73 (1 H, d, J=12.65 Hz). MS (ESI) m/z: 529.4 m/z (M+H)⁺. AnalyticalHPLC: RT=5.43 min.

EXAMPLE I-141(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-5-carboxylicacid amide, 2 TFA

I-141-A.(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-5-carboxylic acid, 2 TFA: I-141A was preparedfollowing the procedures described for Example 142 substituting3-bromo-4-methylbenzoic for 4-bromo-3-methylbenzoic acid. MS (ESI) m/z:533.3 m/z (M+H)⁺.

Example I-141. I-141A (0.012 g, 0.016 mmol) was dissolved in DMF (1 mL).Hunig's base (0.028 mL, 0.158 mmol) was added, followed by ammoniumchloride (8.43 mg, 0.158 mmol), HOBT (2.90 mg, 0.019 mmol) and EDC (3.63mg, 0.019 mmol). The reaction was stirred at room temperature for 48 h,stripped to dryness, and residue purified by reverse phasechromatography to provide the title compound as a white solid. ¹H NMR(500 MHz, CD₃OD) δ ppm 9.53 (1 H, s), 8.87 (1 H, d, J=5.50 Hz), 8.00 (1H, d, J=2.20 Hz), 7.91-7.98 (2 H, m), 7.86 (1 H, d, J=7.70 Hz),7.65-7.70 (2 H, m), 7.59 (1 H, d, J=8.25 Hz), 7.18 (1 H, d, J=15.40 Hz),6.80 (1 H, d, J=15.95 Hz), 5.30 (1 H, dd, J=10.72, 6.32 Hz), 3.24-3.29(1 H, m), 2.95-3.06 (1 H, m), 1.98-2.22 (3 H, m), 1.80-1.96 (1 H, m),1.58-1.78 (2 H, m), 1.24-1.44 (1 H, m), 0.76-1.00 (1 H, m). MS (ESI)m/z: 532.4 (M+H)⁺. Analytical HPLC: RT=4.94 min.

EXAMPLE I-142(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-4-carboxylicacid, 2TFA

I-142A. tert-Butyl 4-bromo-3-methylbenzoate: To a suspension of4-bromo-3-methylbenzoic acid (2.8 g, 13.02 mmol) in THF (20 mL) andhexane (20 mL) in an ice bath under N₂, was added tert-butyl2,2,2-trichloroacetimidate (3.50 mL, 19.53 mmol). After 10 min, BF₃.OEt₂(0.165 mL, 1.302 mmol) was added. The resulting mixture was allowedslowly to warm to rt and stirred overnight. The mixture was diluted withEt₂O, washed with 1.5 M K₂HPO₄ solution, dried over anh. Na₂SO₄,filtered and evaporated. The residue was triturated with 20%Et₂O/hexane, and the solid was filtered off. Filtrate was evaporated.Residue was purified by flash chromatography to provide I-142A as alight peach color oil (2.141 g, 60.6%). MS (ESI) m/z: 293.1/295.1(M+Na)⁺271.2/273.1 (M+H)⁺215.1/217.1 (M+H-tBu)⁺.

I-142B. tert-Butyl 4-bromo-3-formylbenzoate: I-142A (2.14 g, 7.89 mmol)was dissolved in CCl₄ (39.5 ml) and NBS (3.09 g, 17.36 mmol) and benzoylperoxide (0.191 g, 0.789 mmol) were added. The mixture was stirred undernitrogen at reflux in a 90° C. oil bath overnight. Reaction was dilutedwith EtOAc and washed with water and brine, dried over anh. Na₂SO₄,filtered and evaporated. Crude product (3.39 g, 7.90 mmol) was dissolvedin morpholine (10 ml, 115 mmol), and the mixture was heated withstirring in a 60° C. oil bath under nitrogen overnight. After cooling toroom temperature, the mixture was diluted with EtOAc, then stirred for˜30 min. Solids were removed by filtration and washed with EtOAc. Thefiltrate was transferred to a separatory funnel and washed 3× with 5%aq. citric acid and once with brine, then dried over anh. Na₂SO₄,filtered and evaporated. The residue was purified by flashchromatography to provide I-142B as a white solid (1.885 g, 84%). ¹H NMR(500 MHz, CDCl₃) δ ppm 10.39 (1 H, s) 8.47 (1 H, d, J=2.20 Hz) 8.05 (1H, dd, J=8.25, 2.20 Hz) 7.73 (1 H, d, J=8.53 Hz) 1.61 (9 H, s).

I-142C. tert-Butyl 4-bromo-3-(1-hydroxyethyl)benzoate: I-142B wasdissolved in THF (50 mL) and cooled in a dry ice/acetone bath. To thecold solution was added methylmagnesium chloride (3.0 M in THF, 2.86 ml,8.59 mmol) dropwise over 10-15 min. Stirring was continued at −78° C.for 1 h at which point the reaction was quenched with 10% aqueous KHSO₄solution and warmed to room temperature. The mixture was diluted withwater and extracted 3× with EtOAc. Extracts were combined and washedwith water and brine, dried over anh. Na₂SO₄, filtered and evaporated.Residue was purified by flash chromatography to provide the desiredproduct (1.18 g, 59.6%) along with recovered starting material (0.425g,22%). MS (ESI) m/z: 301.1/303.1 (M+H)⁺245.1/247.1 (M+H-tBu)⁺.

I-142D. tert-Butyl 3-acetyl-4-bromobenzoate: I-142C (1.186 g, 3.94 mmol)was dissolved in DCM (50 ml) and treated with PCC (1.02 g, 4.73 mmol)with stirring under nitrogen. The resulting mixture was stirred at roomtemperature for 4 h then filtered through a pad of CELITE®. Filtrate wasevaporated to dryness, and residue was purified by flash chromatographyto provide the product as a colorless liquid (0.938g, 80%). ¹H NMR (500MHz, CDCl₃) δ ppm 8.04 (1 H, d, J=2.20 Hz) 7.88 (1 H, dd, J=8.25, 2.20Hz) 7.67 (1 H, d, J=8.25 Hz) 2.65 (3 H, s) 1.59 (9 H, s).

I-142E. tert-Butyl 4-bromo-3-(2-bromoacetyl)benzoate: I-142D (0.209 g,0.699 mmol) was dissolved in THF (3.5 ml) and pyridinium tribromide(0.226 g, 0.706 mmol) was added with stirring under nitrogen. Mixturewas stirred at room temperature for ˜30 min. Reaction was diluted withEtOAc and washed with brine, dried over anh. Na₂SO₄, filtered andevaporated. The residue was purified by flash chromatography to yieldI-142E (0.214g, 81%) contaminated with a small amount of startingmaterial. MS (ESI) m/z: 323.0 (M+H-tBu)⁺.

Example 142. I-142E was converted into the title compound using the sameseries of steps described for conversion of I-140F into Example 140. ¹HNMR (500 MHz, CD₃OD) δ ppm 9.52 (1 H, s) 8.29 (1 H, d, J=1.65 Hz)7.95-8.03 (2 H, m) 7.64-7.74 (2 H, m) 7.59 (1 H, d, J=8.53 Hz) 7.43 (1H, d, J=8.53 Hz) 7.18 (1 H, d, J=15.68 Hz) 6.78 (1 H, d, J=15.68 Hz)5.28 (1 H, dd, J=10.45, 6.33 Hz) 3.07-3.17 (1 H, m) 2.83-2.94 (1 H, m)2.10-2.26 (1 H, m) 1.86-2.05 (3 H, m) 1.55-1.72 (2 H, m) 1.32-1.45 (1 H,m) 0.78-0.95 (1 H, m). MS (ESI) m/z: 533.2 (M+H)⁺ Analytical HPLC:RT=5.71 min.

TABLE I-8 Examples I-128 to I-142 HPLC Ex. LCMS RT # Structure [M + H]⁺(min) I-128

568.4 4.2 I-129

549.3 4.7 I-130

624.3 5.7 I-131

664.4 6.2 I-132

620.3 6.0 I-133

575.2 7.2 I-134

577.2 6.4 I-135

578.0 7.2 I-136

543.3 4.8 I-137

586.2 5.7 (B) I-138

698.1 10.0 I-139

644.3 5.9 I-140

529.4 5.4 I-141

532.4 4.9 I-142

533.0 5.7

Examples I-143 to I-147 were prepared following the sequence ofprocedures described in step 10H, by replacing 10G with 39A; followed bystep 15D, by replacing Intermediate 2 with appropriately substitutedcarboxylic acid derivatives (R—CO₂H). Examples I-148 to I-157 wereprepared following the sequence of procedures described in step 10H, byreplacing 10G with 39A; followed by step 15D, by replacing Intermediate2 with appropriately substituted carboxylic acid derivatives (R—CO₂H);and finally Boc-deprotection according to the procedure described in 3C.Examples I-158 to I-161 were prepared by coupling 76B with appropriatelysubstituted carboxylic acid derivatives (R—CO₂H) using couplingconditions described in step 15D. In the case of Example I-158, anadditional Boc-deprotection step as described in step 3C was required.Examples I-162 to I-176 were prepared in a similar manner as describedabove.

TABLE I-9 Examples I-143 to I-176

HPLC Ex. LCMS RT (min) # R R³ [M + H]⁺ (method) I-143

H 480.2 4.2 (D) I-144

H 510.1 3.6 (D) I-145

H 474.1 3.8 (D) I-146

H 512.1 3.8 I-147

H 526.2 4.4 I-148

H 489.2 3.0 (D) I-149

H 507.1 3.0 (D) I-150

H 495.2 6.3 (C) I-151

H 515.2 7.4 (C) I-152

H 529.2 8.3 (C) I-153

H 529.2 8.3 (C) I-154

H 515.2 7.7 (C) I-155

H 515.2 7.7 (C) I-156

H 502.2 6.4 (C) I-157

H 525.2 6.7 (C) I-158

Cl 536.1 3.5 I-159

Cl 584.0 5.0 I-160

Cl 545.2 5.2 I-161

Cl 584.0 6.1 I-162

F 606.0 7.1 I-163

F 498.2 7.7 I-164

F 568.2 5.3 I-165

F 543.1 3.5 I-166

F 600.2 10.1  I-167

F 568.2 8.1 I-168

F 602.1 6.4 I-169

F 494.3 4.0 I-170

F 584.4 [M − H]⁺ 6.1 I-171

Me 602.2 4.8 I-172

Me 494.3 5.3 I-173

Me 620.3 5.2 I-174

Me 559.3 6.4 I-175

Me 600.3 6.0 I-176

CN 613.2 6.9

EXAMPLE I-177N-((E)-(S)-5-Acetylamino-18-chloro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-2,6-difluoro-4-methyl-benzamide,TFA

I-177A and 177-B.(E)-(S)-5,15-Diamino-18-chloro-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-9-oneand((E)-(S)-15-amino-18-chloro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl)-carbamicacid ethyl ester: 76B (0.377g, 0.815 mmol) was dissolved in a mixture ofethanol (3.3 ml), water (9.8 ml), and THF (3.3 ml), and LiOH (0.156 g,6.52 mmol) was added. The reaction was stirred at 60° C. for 48 h,cooled to room temperature, neutralized with 1M HCl and concentrated.The crude products were isolated by reverse phase chromatography toprovide I-177A (0.559 g) and I-177B (30 mg) which were used withoutfurther purification.

I-177C. 2,5-Dioxopyrrolidin-1-yl 2,6-difluoro-4-methylbenzoate: To asolution of 2,6-difluoro-4-methylbenzoic acid (2.0 g, 11.62 mmol) in THF(61.8 mL) was added 1-hydroxypyrrolidine-2,5-dione (1.471 g, 12.78 mmol)and 1,3-diisopropylcarbodiimide (2.00 mL, 12.78 mmol) at rt. Thereaction mixture was stirred under N₂ at rt overnight. Reaction mixturewas filtered, and the filtrate was evaporated. The residue wasresuspended in MeOH, filtered, and washed several times with MeOH. Theremaining white solid was dried under vacuum to yield I-177C (2.80 g,90%). MS (ESI) m/z: 155.1 (M+H)⁺.

I-177D (Example I-184.N-((E)-(S)-5-Amino-18-chloro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-2,6-difluoro-4-methyl-benzamide):I-177D was prepared from I-177A following the procedure described instep 1G, by replacing Intermediate 1 with 1-177C. ¹H NMR (500 MHz,CD₃OD) δ ppm 7.17 (1 H, d, J=8.25 Hz), 6.89 (2 H, d, J=8.80 Hz), 6.68 (1H, dd, J=8.25, 2.20 Hz), 6.60 (1 H, d, J=2.20 Hz), 5.49-5.61 (1 H, m),5.23-5.34 (1 H, m), 5.14 (1 H, dd, J=9.35, 3.85 Hz), 2.55-2.66 (1 H, m),2.41-2.52 (1 H, m), 2.33-2.41 (7 H, m). MS (ESI) m/z: 486.1 (M+H)⁺.Analytical HPLC: RT=4.92 min.

Example I-177. I-177D (0.03 g, 0.062 mmol) was dissolved in DCM (0.5 ml)and a solution of acetic anhydride (6.30 mg, 0.062 mmol) in DCM (0.1 mL)was added dropwise. The reaction was stirred overnight at roomtemperature. Reaction mixture was concentrated, and residue was purifiedby reverse phase chromatography to provide the title compound (12.6 mg,31.6%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.45 (1 H, br.s.), 10.08-10.13 (1 H, m), 9.32 (1 H, br. s.), 9.21 (1 H, d, J=7.70 Hz),7.63 (1 H, br. s.), 7.44 (1 H, d, J=10.45 Hz), 7.33 (1 H, d, J=8.25 Hz),6.98 (2 H, d, J=8.80 Hz), 5.41-5.61 (1 H, m), 5.20-5.35 (1 H, m),5.04-5.19 (1 H, m), 2.39-2.45 (1 H, m), 2.32 (3 H, s), 2.29-2.40 (2 H,m), 2.16-2.31 (2 H, m), 2.04 (3 H, s). MS (ESI) m/z: 528.2 (M+H)⁺.Analytical HPLC: RT=6.05 min.

EXAMPLE I-178[(E)-(S)-18-Chloro-15-(2,6-difluoro-4-methyl-benzoylamino)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]-carbamicacid 2-methoxy-ethyl ester, TFA

I-177C was dissolved in DCM (5 mL) and pyridine (0.02 mL, 0.247 mmol)was added, followed by dropwise addition of a solution of 2-methoxyethylcarbonochloridate (8.55 mg, 0.062 mmol) in DCM (0.5 mL). The resultingmixture was stirred overnight at room temperature. The reaction wasconcentrated to dryness, and residue purified by reverse phase HPLC toprovide Example I-178 as a white solid (10.6 mg, 24.21%). ¹H NMR (500MHz, DMSO-d₆) δ ppm 11.38 (1 H, br. s.), 9.96 (1 H, br. s.), 9.33 (1 H,br. s.), 9.22 (1 H, d, J=8.25 Hz), 7.45 (1 H, br. s.), 7.35-7.41 (1 H,m), 7.27-7.35 (1 H, m), 6.99 (2 H, d, J=8.25 Hz), 5.45-5.58 (1 H, m),5.20-5.34 (1 H, m), 5.05-5.18 (1 H, m), 4.17-4.27 (2 H, m), 3.47-3.61 (2H, m), 3.27 (3 H, s), 2.43-2.50 (2 H, m), 2.31-2.38 (2 H, m), 2.33 (3 H,s), 2.18-2.28 (2 H, m). MS (ESI) m/z: 588.3 (M+H)⁺. Analytical HPLC:RT=6.8 min.

EXAMPLE I-179[(E)-(S)-18-Chloro-15-(2,6-difluoro-4-methyl-benzoylamino)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]-carbamicacid ethyl ester, TFA

Example I-179 was prepared following the procedure described for I-177Dby replacing I-177A with 1-177B. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.26(1 H, br. s.), 9.65 (1 H, s), 9.19 (1 H, br. s.), 9.00 (1 H, d, J=7.70Hz), 7.50 (1 H, br. s.), 7.38-7.45 (1 H, m), 7.31-7.36 (1 H, m),6.92-7.03 (2H, m), 5.49-5.62 (1 H, m), 5.23-5.36 (1 H, m), 5.07-5.22 (1H, m), 4.16 (2 H, q, J=6.97 Hz), 2.40-2.50 (2 H, m), 2.33-2.43 (5 H, m),2.25-2.33 (2 H, m), 1.27 (3H, t, J=7.02 Hz). MS (ESI) m/z: 558.2 (M+H)⁺.Analytical HPLC: RT=7.35 min.

EXAMPLE I-180[(E)-(S)-18-Chloro-15-(2,6-difluoro-4-methyl-benzoylamino)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]-carbamicacid (R)-1-(tetrahydro-furan-2-yl)methyl ester, TFA

I-180A. (R)-4-Nitrophenyl (tetrahydrofuran-2-yl)methyl carbonate: Asolution of 4-nitrophenyl carbonochloridate (0.2 g, 1.998 mmol) in DCM(8 mL) was added dropwise to a solution of(R)-hydroxy(tetrahydrofuran-2-yl)methylium (0.2 g, 1.998 mmol) in DCM(6.66 ml)/pyridine (0.162 ml, 1.998 mmol) at 0° C. The reaction wasmaintained at 0° C. for 2 hours then allowed to warm to RT overnight.Reaction was quenched with water and diluted with DCM. Organic phase waswashed 3× with sat'd. sodium bicarbonate, and once with brine, driedover sodium sulfate, filtered and concentrated. I-180A (0.442 g, 83%),was obtained as a white solid. MS (ESI) m/z: 290.2 (M+Na)⁺

Example I-180. I-177D (0.026 g, 0.054 mmol) was dissolved in pyridine.I-180A (0.029 g, 0.107 mmol) was added followed by DMAP (6.54 mg, 0.054mmol). Reaction was stirred at RT overnight. Another 2 equiv. of I-180Awas added, and the mixture was stirred for 2 more hours, thenevaporated. Residue was purified by reverse phase chromatography toprovide the title compound (5.6 mg, 13.80%) as a white solid. ¹H NMR(500 MHz, CD₃OD) δ ppm 9.63 (1 H, br. s.), 7.55 (1 H, s), 7.36-7.46 (2H, m), 6.91 (2 H, d, J=8.80 Hz), 5.45-5.64 (1 H, m), 5.29-5.46 (1 H, m),5.06-5.23 (1H, m), 4.04-4.32 (3 H, m), 3.85-3.96 (1 H, m), 3.70-3.84 (1H, m), 2.70-2.84 (1 H, m), 2.21-2.62 (8 H, m), 2.00-2.14 (1 H, m),1.81-2.01 (2 H, m), 1.52-1.80 (1 H, m). MS (ESI) m/z: 614.2 (M+H)⁺.Analytical HPLC: RT=7.65 min.

EXAMPLES I-181[(E)-(S)-18-Chloro-15-(2,6-difluoro-4-methyl-benzoylamino)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]-carbamicacid pyridin-2-ylmethyl ester, TFA

and

EXAMPLE I-182N-[(E)-(S)-18-Chloro-9-oxo-5-(2,2,2-trifluoro-acetylamino)-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl]-2,6-difluoro-4-methyl-benzamide,TFA

I-177D (0.013 g, 0.018 mmol) was dissolved in DCM (0.5 ml). TEA (0.018ml, 0.127 mmol) was added, followed by triphosgene (10.81 mg, 0.036mmol). The mixture was stirred for 30 min at RT, and then a solution ofpyridin-2-ylmethanol (9.93 mg, 0.091 mmol) in DCM (0.1 mL) was added.Stirring was continued at RT overnight. Reaction mixture was evaporated,and residue was purified by reverse phase chromatography to provideExample I-181 (1.6 mg, 9.83%). ¹H NMR (500 MHz, CD₃OD) δ ppm 8.68 (1 H,d, J=4.95 Hz), 8.22 (1 H, td, J=7.84, 1.37 Hz), 7.82 (1 H, d, J=7.70Hz), 7.64-7.70 (1H, m), 7.56-7.60 (1 H, m), 7.43-7.46 (2 H, m), 6.91 (2H, d, J=8.80 Hz), 5.47-5.61 (1 H, m), 5.41 (2 H, s), 5.26-5.40 (1 H, m),5.08-5.17 (1 H, m), 2.67-2.80 (1 H, m), 2.26-2.55 (8 H, m). MS (ESI)m/z: 623.1 (M+H)⁺. Analytical HPLC: RT=5.31 min., and Example I-182 (5.6mg, 43.8%). ¹H NMR (500 MHz, CD₃OD) δ ppm 7.79 (1 H, d, J=2.20 Hz), 7.65(1 H, dd, J=8.53, 2.20 Hz), 7.56 (1 H, d, J=8.53 Hz), 6.91 (2 H, d,J=8.80 Hz), 5.48-5.60 (1 H, m), 5.32-5.44 (1 H, m), 5.09-5.19 (1 H, m),2.69-2.79 (1 H, m), 2.29-2.57 (8 H, m). MS (ESI) m/z: 582.3 (M+H)⁺.Analytical HPLC: RT=8.06 min.

EXAMPLE 183[(E)-(S)-18-Chloro-15-(2,6-difluoro-4-methyl-benzoylamino)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]-carbamicacid 2-dimethylamino-ethyl ester, 2 TFA

Example I-183 was prepared using the procedure described for ExampleI-181 by replacing pyridin-2-ylmethanol with 2-(dimethylamino)ethanol.¹H NMR (500 MHz, CD₃OD) δ ppm 8.10 (1 H, s), 7.58 (1 H, s), 7.44-7.47(2H, m), 6.90 (2 H, d, J=8.80 Hz), 5.49-5.59 (1 H, m), 5.28-5.41 (1 H,m), 5.07-5.15 (1 H, m), 4.49-4.55 (2 H, m), 3.46-3.56 (2 H, m), 3.00 (6H, s), 2.60-2.75 (2 H, m), 2.25-2.56 (7 H, m). MS (ESI) m/z: 601.3(M+H)⁺. Analytical HPLC: RT=4.66 min.

EXAMPLE 185[(E)-(S)-18-Chloro-15-(2,6-difluoro-4-methyl-benzoylamino)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]-carbamicacid azetidin-3-yl ester, 2 TFA

Example 186 was dissolved in DCM (1 mL) and TFA (0.25 mL) was added.After stirring for 1h at RT, the reaction mixture was evaporated todryness to provide the title compound. ¹H NMR (500 MHz, CD₃OD) δ ppm7.44-7.50 (1 H, m), 7.33-7.41 (2 H, m), 6.80-6.86 (2 H, m), 5.38-5.52 (1H, m), 5.23-5.34 (2 H, m), 5.00-5.07 (1 H, m), 4.33-4.43 (2 H, m),4.09-4.19 (2 H, m), 2.61-2.73 (1 H, m), 2.17-2.49 (8 H, m). MS (ESI)m/z: 585.2 (M+H)⁺. Analytical HPLC: RT=4.53 min.

EXAMPLE 1863-[(E)-(S)-18-Chloro-15-(2,6-difluoro-4-methyl-benzoylamino)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-ylcarbamoyloxy]-azetidine-1-carboxylicacid tert-butyl ester, TFA

Example 186 was prepared using the procedures described for Ex. I-180,by replacing (R)-hydroxy(tetrahydrofuran-2-yl)methylium with tert-butyl3-hydroxyazetidine-1-carboxylate in step I-180A. ¹H NMR (500 MHz, CD₃OD)δ ppm 9.81 (1 H, br. s.), 7.52-7.58 (1 H, m), 7.37-7.48 (2 H, m), 6.90(2 H, d, J=8.80 Hz), 5.45-5.59 (1 H, m), 5.29-5.41 (1 H, m), 5.16-5.24(1 H, m), 5.07-5.16 (1 H, m), 4.23-4.35 (2 H, m), 3.85-3.99 (2 H, m),2.68-2.78 (1 H, m), 2.25-2.56 (8 H, m), 1.44 (9 H, s). MS (ESI) m/z:685.3 (M+H)⁺. Analytical HPLC: RT=8.63 min.

EXAMPLE I-187[(E)-(S)-18-Chloro-15-(2,6-difluoro-4-methyl-benzoylamino)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-ylcarbamoyloxy]-aceticacid, TFA

Example I-187 was prepared following the procedure described for Example181, by replacing pyridin-2-ylmethanol with ethyl 2-hydroxyacetate,followed by hydrolysis of the crude ethyl ester with LiOH in THF. ¹H NMR(500 MHz, CD₃OD) δ ppm 9.80 (1 H, br. s.), 7.57 (1 H, s), 7.43 (2 H, s),6.90 (2H, d, J=8.80 Hz), 5.47-5.62 (1 H, m), 5.29-5.41 (1 H, m),5.01-5.20 (1 H, m), 4.66 (2 H, s), 2.68-2.79 (1 H, m), 2.25-2.56 (8 H,m). MS (ESI) m/z: 588.2 (M+H)⁺. Analytical HPLC: RT=6.08 min.

EXAMPLE I-188[(E)-(S)-18-Chloro-15-(2,6-difluoro-4-methyl-benzoylamino)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]-carbamicacid 2-tert-butoxy-ethyl ester, TFA

Example 188 was prepared similarly to Ex. I-180, by replacing(R)-hydroxy(tetrahydrofuran-2-yl)methylium with 2-tert-butoxyethanol instep I-180A ¹H NMR (500 MHz, CD₃OD) δ ppm 9.51 (1 H, br. s.), 7.50 (1 H,s), 7.37 (2 H, s), 6.86 (2 H, d, J=8.80 Hz), 5.40-5.58 (1 H, m),5.22-5.33 (1 H, m), 5.08 (1 H, dd, J=10.17, 4.12 Hz), 4.13-4.21 (2 H,m), 3.56-3.64 (2 H, m), 2.59-2.70 (1 H, m), 2.34 (8 H, s), 1.17 (9 H,s). MS (ESI) m/z: 630.3 (M+H)⁺. Analytical HPLC: RT=8.0 min.

EXAMPLE I-189[(E)-(S)-18-Chloro-15-(2,6-difluoro-4-methyl-benzoylamino)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]-carbamicacid 2-hydroxy-ethyl ester, TFA

I-189A. 2-tert-Butoxyethyl carbonochloridate: To a solution of2-tert-butoxyethanol (0.444 mL, 3.38 mmol) and pyridine (0.274 mL, 3.38mmol) in ether (10 mL) was added triphosgene (0.331 g, 1.117 mmol)dissolved in 2 mL of ether. The reaction mixture was maintained at 0° C.for one hour. Reaction mixture was filtered and concentrated to providethe crude 2-tert-butoxyethyl carbonochloridate (0.424 g, 69.3%), as aclear oil. ¹H NMR (500 MHz, CDCl₃) δ ppm 4.38-4.43 (2 H, m), 3.60-3.65(2 H, m), 1.20 (9 H, s).

Example I-189. This compound was prepared from I-177D according to theprocedure described for step I-123B, by replacing 2-methoxyethylcarbonochloridate with I-189A, followed by deprotection of the crudet-butyl ether with TFA/DCM. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.57 (1 H, br.s.), 7.55-7.66 (1 H, m), 7.39-7.51 (2 H, m), 6.94 (2 H, d, J=8.80 Hz),5.48-5.61 (1 H, m), 5.32-5.46 (1 H, m), 5.16 (1 H, dd, J=10.59, 4.54Hz), 4.21-4.34 (2 H, m), 3.77-3.86 (2 H, m), 2.74-2.84 (1 H, m),2.31-2.59 (8 H, m). MS (ESI) m/z: 574.2 (M+H)⁺. Analytical HPLC: RT=5.77min.

EXAMPLE 190[(E)-(S)-18-Chloro-15-(2,6-difluoro-4-methyl-benzoylamino)-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]-carbamicacid tetrahydro-furan-3-ylmethyl ester, TFA

Example I-190 was prepared following the procedures described for Ex.I-189, by replacing 2-tert-butoxyethanol with(tetrahydrofuran-3-yl)methanol in step I-189A and omitting the TFAtreatment. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.54 (1 H, br. s.), 8.25 (1 H,d, J=9.35 Hz), 7.47-7.53 (1 H, m), 7.24-7.45 (2 H, m), 6.85 (2 H, d,J=8.80 Hz), 5.41-5.57 (1 H, m), 5.24-5.35 (1 H, m), 5.06 (1 H, dd,J=10.72, 4.12 Hz), 4.06-4.28 (1 H, m), 3.94-4.04 (1 H, m), 3.74-3.87 (2H, m), 3.63-3.73 (1 H, m), 3.53-3.62 (1 H, m), 2.62-2.74 (1 H, m),2.53-2.63 (1 H, m), 2.20-2.50 (8 H, m), 1.90-2.10 (1 H, m), 1.58-1.75 (1H, m). MS (ESI) m/z: 614.3 (M+H)⁺. Analytical HPLC: RT=6.86 min.

TABLE I-10 Examples I-177 to I-190

HPLC Ex. LCMS RT # R [M + H]⁺ (min) I-177

528.2 6.1 I-178

588.3 6.8 I-179

558.2 7.3 I-180

614.2 7.7 I-181

621.3 5.3 I-182

582.3 8.1 I-183

601.3 4.7 I-184 H 486.1 4.9 I-185

585.2 4.5 I-186

685.3 8.6 I-187

588.2 6.1 I-188

630.3 8.0 I-189

574.2 5.8 I-190

614.3 6.9

Example I-192 was prepared following the procedure described in Example47. Examples I-193 to I-195 were prepared following the proceduresdescribed in Example 53, by replacing 15B with 10C.

EXAMPLE I-196{(E)-(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-11-hydroxy-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl}-carbamicacid methyl ester, trifluoroacetic acid salt

I-196A.{3-Amino-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester (0.15g, 0.28 mmol) was dissolved in DMF (3 mL). Tothis solution was added 3-Hydroxy-pent-4-enoic acid (0.064g, 0.55 mmol),followed by T3P (0.326g, 0.423 mmol) and Hunig's base (0.073g, 0.56mmol) and the reaction mixture was stirred at room temperatureovernight. Quenched the reaction with water (100 ml), and extractedorganics with EtOAc (2×100 mL), dried (MgSO₄) and evaporated to agreenish semi-solid mass. Purified the crude via normal phasechromatography. Pure fractions were collected and concentrated to a paleyellow solid (0.11 g, 62%). ¹H NMR (500 MHz, CD₃OD) δ ppm 8.39 (m, 1H),7.58-7.43 (m, 2H), 7.21 (s, 1H), 5.80 (m, 1H), 5.55-5.05 (m, 8H), 3.76(s, 3H), 3.54 (m. 2H), 2.80 (m, 2H), 1.46 (s, 9H), 0.94 (m, 2H), 0.00(s, 9H). MS (ESI) m/z: 630.3 (M+H)⁺.

I-196 B. The product from I-196A was dissolved in DCM (35 mL) anddegassed. After 0.5 h pTsOH (0.03g, 0.18 mmol) was added and thereaction mixture was stirred for an additional 0.5h while beingdegassed. To this solution was added Grubbs II catalyst (0.06g, 0.07mmol) and the reaction mixture was heated to 40° C. overnight. Reactionmixture was cooled and quenched with sodium phase phase solution (10%,50 mL) and the organics layer separated. The aqueous layer was furtherextracted with EtOAc (2×100 ml), and the combined extracts was dried(MgSO₄) and evaporated to a brown oil. The crude material was purifiedvia normal phase chromatography to afford the desired macrocycle as acolorless oil. MS (ESI) m/z: 602.2 (M+H)⁺.

I-196C. The removal of the Boc and Sem protecting groups as in Example 1(step 1F) of the product from I-196B, followed by the coupling of thecrude amino macrocycle with Intermediate 1 as described for Example 1(step 1G) afforded the title compound as a white solid (10 mg, 23%). ¹HNMR (500 MHz, CD₃OD) δ ppm 9.55 (s, 1H), 9.50 (d, J=2.5 Hz, 1H), 7.98(m, 1H), 7.69 (dd, J=2.3 & 8.5 Hz, 1H), 7.60-7.57 (m, 2H), 7.41-7.37 (m,2H), 7.18-7.13 (dd, J=4.3 & 8.7 Hz, 1H), 6.77 (d, J=15.8 Hz, 1H),5.84-5.73 (m, 1H), 5.55-5.43 (m, 1H), 5.17-5.09 (m, 1H), 4.44 (m, 1H),3.75 (s, 3H), 2.9-2.45 (m, 5H). MS (ESI) m/z: 604.3 (M+H)⁺. AnalyticalHPLC: RT=5.12 min.

Example I-197{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-11-hydroxy-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, trifluoroacetic acid salt

The reduction of I-196B as in Example 2 (step 2G), deprotection of theBoc and Sem protecting groups as in Example 1 (step 1F), and couplingwith Intermediate 1 as described for Example 1 (step 1G) afforded thetitle compound as a brown solid (7 mg, 13%). ¹H NMR (500 MHz, CD₃OD) δppm 9.51 (s, 1H), 9.51 (s, 1H), 7.98 (dd, J=2.3 & 8.3 Hz, 1H), 7.69-7.66(m, 1H), 7.61-7.56 (m, 1H), 7.44-7.41 (m, 2H), 7.16-7.10 (t, 1H),6.79-6.69 (dd, J=15.6 Hz, 2H), 5.05-4.97 (m, 1H), 4.00 (m, 1H), 3.76 (s,3H), 2.66-2.63 (m, 1H), 2.34-2.22 (m, 2H), 2.05 (m, 1H), 1.80 (m, 1H),1.62 (m, 1H), 1.58 (m, 1H), 1.38-1.22 (m, 2H), 1.00-0.74 (m, 2H). MS(ESI) m/z: 606.4 (M+H)⁺. Analytical HPLC: RT=4.36 min.

EXAMPLE I-198{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9,11-dioxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, trifluoroacetic acid salt

The reduction of I-196B as in Example 2 (step 2G), followed by theoxidation of the reduced product (0.04g, 0.06 mmol) with Dess-Martinperiodinane (0.03g, 0.076 mmol) in DCM (5 mL), deprotection of the Bocand SEM protecting groups as in Example 1 (step 1F), and coupling withIntermediate 1 as described for Example 1 (step 1G) afforded the titlecompound as a brown solid (6 mg, 15%). ¹H NMR (500 MHz, CD₃OD) δ ppm9.41 (s, 1H), 7.87 (d, J=2.7 Hz, 1H), 7.52-7.45 (m, 4H), 7.40-7.30 (m,4H), 7.04 (d, J=16.4 Hz, 1H), 6.65 (d, J=15.4 Hz, 1H), 4.97 (m, 1H),3.66 (s, 3H), 3.63 (t, 1H). 3.18-3.10 (m, 1H), 2.25-2.05 (m, 2H), 1.75(bm, 2H). MS (ESI) m/z: 604.2 (M+H)⁺. Analytical HPLC: RT=5.79 min.

EXAMPLE I-199 Acetic acid(S)-15-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-methoxycarbonylamino-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-11-ylester, trifluoroacetic acid salt

The reduction of I-196B as in Example 2 (step 2G), followed by theacetylation with acetic anhydride of the reduced product, deprotectionof the Boc and SEM protecting groups as in Example 1 (step 1F), andcoupling with Intermediate 1 as described for Example 1 (step 1G)afforded the title compound as a brown solid (4 mg, 5%). ¹H NMR (500MHz, CD₃OD) δ ppm 9.39 (s, 1H), 7.88-7.85 (dd, J=2.3 & 8.8 Hz, 1H),7.63-7.56 (m, 1H), 7.54-7.47 (m, 2H), 7.48-7.39 (m, 2H), 7.08-7.03 (m,1H), 6.69-6.57 (q, 2H), 5.12-4.98 (m, 1H), 4.48 (m, 1H), 3.66 (s, 3H),2.78 (dd, 2H), 2.40-2.30 (m, 1H), 2.12 (bm, 1H), 1.95 (s, 3H), 1.51-1.00(m, 4H). MS (ESI) m/z: 648.2 (M+H)⁺. Analytical HPLC: RT=4.93 min.

Examples I-200 and I-201 were prepared following the proceduresdescribed in step 10D, by replacing but-3-enoic acid with2-methylpent-4-enoic acid; followed by steps 2E/2F; 10H; and 1G.Examples I-202 and I-203 were prepared following the proceduresdescribed in step 10D, by replacing but-3-enoic acid with2-methylpent-4-enoic acid; followed by steps 2E/2F; 2G; 10H; and 1G.

EXAMPLES I-205 and I-206{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acroyoylamino]-11-methyl-8-oxa-17,19-diaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, TFA, Diastereomer A and Diastereomer B

I-205A. Methyl 2-hydroxy-4-(methoxycarbonylamino)benzoate: Methyl4-amino-2-hydroxybenzoate (10 g, 59.8 mmol) was dissolved in DCM (120mL), and pyridine (5.32 mL, 65.8 mmol) was added. The mixture was cooledto 0° C., and methyl chloroformate (4.87 mL, 62.8 mmol) was addeddropwise. The reaction was stirred for 1.5h, then quenched with 1.5Mdibasic potassium phosphate solution, and extracted 2× with DCM. Thecombined org. phases were washed 2× with 1M HCl and 1× with brine, driedwith sodium sulfate, filtered and concentrated to yield I-205A (14.2 g)which was used without further purification in the next step. MS (ESI)m/z: 226.2 (M+H)⁺.

I-205B. Methyl 2-(allyloxy)-4-(methoxycarbonylamino)benzoate: I-205A(14.22 g, 63.1 mmol) was dissolved in acetone (210 mL). Allyl bromide(16.39 mL, 189 mmol) was added followed by potassium carbonate (43.6 g,316 mmol). The reaction was heated at 60° C. under Ar and a refluxcondensor for 8 hours. The reaction was concentrated under reducedpressure and diluted with EtOAc/water. The aq. phase was washed withEtOAc 2×, then the combined organic phases were washed with brine anddried with sodium sulfate and concentrated. Residue was purified bynormal phase chromatography to provide I-205B (8.03 g, 47.9%), as ayellow solid. MS (ESI) m/z: 266.1 (M+H)⁺

I-205C. Methyl 3-(allyloxy)-4-(2-chloroacetyl)phenylcarbamate: Totrimethylsulfoxonium chloride (12.12 g, 94 mmol) and 1 M potassiumt-butoxide (99 mL, 99 mmol) was added an additional 80 mL of THF. Themixture was refluxed for 2 hours, then allowed to cool to roomtemperature. A solution of I-205B (5 g, 18.85 mmol) dissolved in 100 mLof THF was added dropwise. The reaction was allowed to stir at RTovernight under Ar. The reaction mixture and was concentrated, and theresidue was partitioned between EtOAc and water. Aqueous phase wasextracted 2× with EtOAc. Combined organic phases were washed with brine,dried with sodium sulfate, filtered and concentrated. Residue was takenup in methylene chloride and filtered. Filtrate was purified by normalphase chromatography, and fractions containing product combined with theinsoluble solid above to provide the intermediate sulfonium species(5.76 g, 94%, MS (ESI) m/z: 326.1 (M+H)⁺), which was dissolved in THF(89 mL). a solution of 4M HCl in Dioxane (8.85 mL, 35.4 mmol) was added,and the mixture was stirred at 70° C. overnight in a sealed tube. Thereaction mixture was concentrated, and residue was purified by normalphase chromatography to provide I-205C (2.01 g, 40.0%) as a yellowsolid. MS (ESI) m/z: 284.1 (M+H)⁺

I-205D.{3-Allyloxy-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: I-205D was prepared in three steps following theprocedures described for steps 2A, by replacing2-bromo-1-(2-bromophenyl)ethanone with I-205C; 2B; and 10B. MS (ESI)m/z: 573.4 (M+H)⁺.

I-205E.{4-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-hydroxy-phenyl}-carbamicacid methyl ester: I-205D (0.663 g, 1.158 mmol) was dissolved inmethanol (5.79 ml) and added to a 3 neck flask along with potassiumcarbonate (0.480 g, 3.47 mmol). The flask was degassed and backfilledwith Ar 3×. (Ph₃P)₄Pd (0.134 g, 0.116 mmol) was added under a stream ofAr. The mixture was degassed and backfilled 3 more times with Ar. Thereaction was stirred for 10 min at RT, then an additional portion ofpotassium carbonate (0.480 g, 3.47 mmol) was added under a stream of Ar,and the mixture was stirred for 1 hr under Ar. Reaction was diluted withEtOAc/water; aq. phase was extracted 2× with EtOAc; combined organicphases were washed with brine, dried with sodium sulfate concentrated.Residue was purified by flash chromatography to provide I-205E (0.45 g,0.845 mmol, 73.0%) as a white solid. MS (ESI) m/z: 533.4 (M+H)⁺.

I-205F. 5-Iodo-3-methylpent-1-ene: To a cooled solution (0° C.) of 1Mlithium aluminum hydride in Et₂O (21.90 mL, 21.90 mmol) and 10 mL ofadditional ether, was added dropwise 3-methylpent-4-enoic acid (1.064mL, 8.76 mmol) dissolved in 15 mL of ether. Reaction was allowed to warmto RT and stirred overnight. The reaction was carefully poured onto icein small portions, and 15 mL of 5M H₂SO₄ was added to dissolve most ofthe salts. The aq. phase was extracted 2× with ether and combinedorganic phases were washed with brine, dried with sodium sulfate,filtered and concentrated to provide the crude 3-methylpent-4-en-1-ol,which was taken on without further purification. The alcohol (0.877 g,8.76 mmol) was dissolved in 20 mL of anhydrous DCM, andtriphenylphosphine (2.99 g, 11.38 mmol) and imidazole (0.894 g, 13.13mmol) were added. The reaction mixture was cooled to 0° C., and asolution of iodine (2.89 g, 11.38 mmol) in 20 mL of DCM was addeddropwise. After 30 min at 0° C., the reaction was warmed to RT andstirred overnight. The reaction was washed 3× with 10% aq. sodiumsulfite and 1× with brine, dried with sodium sulfate, filtered andconcentrated. Residue was purified on a pad of silica gel eluted withpentane to provide the iodide (0.937 g, 4.46 mmol, 50.9%) as a clearoil.

I-205G.[4-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-(3-methyl-pent-4-enyloxy)-phenyl]-carbamicacid methyl ester: I-205E (0.206 g, 0.335 mmol, 79%) was dissolved inacetone (3 mL) and potassium carbonate (0.292 g, 2.112 mmol) and I-205F(0.444 g, 2.112 mmol) were added. Reaction mixture was stirred at 55° C.in a sealed vial for 1h, then at 70° C. overnight. The reaction wasconcentrated and partitioned between water and EtOAc. Aq. phase wasre-extracted 2× with EtOAc, and combined organic extracts were washedwith brine dried with sodium sulfate, filtered and concentrated. Residuewas purified by normal phase chromatography to provide I-205G (0.206 g,79%) as a white solid. MS (ESI) m/z: 615.5 (M+H)⁺.

Examples I-205 and I-206. The title compounds were prepared in foursteps from I-205G using the procedures described in steps 2E/F and 2G,at which point the diastereomers were separated by reverse phasechromatography and carried on individually through the deprotection andamide coupling steps using the procedures described in steps 10H and 1G.Example I-205 (Diastereomer A): ¹H NMR (500 MHz, CD₃OD) δ ppm 9.52 (1 H,s), 7.99 (1 H, d, J=2.20 Hz), 7.69 (1 H, dd, J=8.53, 2.48 Hz), 7.60 (1H, d, J=8.53 Hz), 7.40 (1 H, s), 7.33-7.40 (2 H, m), 7.19 (1 H, d,J=15.41 Hz), 7.02-7.09 (1 H, m), 6.80 (1 H, d, J=15.41 Hz), 5.14 (1 H,dd, J=8.80, 4.40 Hz), 3.99-4.13 (2 H, m), 3.76 (3 H, s), 2.22-2.41 (1 H,m), 1.71-1.91 (3 H, m), 1.55-1.71 (2 H, m), 1.41-1.55 (1 H, m),0.94-1.05 (2 H, m), 0.95 (3 H, d, J=6.60 Hz). MS (ESI) m/z: 591.2(M+H)⁺. Analytical HPLC: RT=6.98 min. Example I-206 (Diastereomer B): ¹HNMR (400 MHz, CD₃OD) δ ppm 9.51 (1 H, s), 7.95 (1 H, d, J=2.20 Hz), 7.67(1 H, dd, J=8.79, 2.20 Hz), 7.52-7.62 (1 H, m), 7.40-7.43 (1 H, m),7.37-7.40 (1 H, m), 7.36 (1H, d, J=8.25 Hz), 7.14 (1 H, d, J=15.39 Hz),7.05 (1 H, dd, J=8.25, 1.65 Hz), 6.70 (1 H, d, J=15.94 Hz), 5.01 (1 H,dd, J=9.89, 4.95 Hz), 3.94-4.12 (2 H, m), 3.75 (3 H, s), 1.99-2.25 (2 H,m), 1.47-1.81 (4 H, m), 0.96-1.34 (3 H, m), 0.94-1.03 (3 H, m). MS (ESI)m/z: 591.2 (M+H)⁺. Analytical HPLC: RT=6.976 min

Examples I-207 and I-208 were prepared in a similar manner as ExamplesI-205 and I-206 starting from Intermediate I-205E and substituting2-methylpent-4-enoic acid for 3-methylpent-4-enoic acid in step I-205F.

Examples I-209 to I-212 were prepared following the procedures describedfor the preparation of Examples 154 and 155, replacing allylmagnesiumbromide with but-3-enylmagnesium bromide. Examples I-213 to I-215 wereprepared following the procedures described for the preparation ofExamples 125, 39, and 34, replacing pent-4-enoic acid with hex-5-enoicacid.

TABLE I-11 Examples I-191 to I-215

HPLC Ex. LCMS RT # L—Y R³ [M + H]⁺ (min) I-191 —(CH₂)₅—C(O)NH— F 608.37.0 I-192

H 602.0 5.4 I-193

H 602.2 5.5 I-194

H 602.2 5.4 I-195

H 602.2 5.4 I-196

H 604.2 5.1 I-197

H 604.4 [M − H]⁺ 4.4 I-198

H 604.2 5.8 I-199

H 648.2 4.9 I-200

H 602.2 5.4 I-201

H 602.3 5.3 I-202

H 604.3 4.9 I-203

H 604.3 4.9 I-204

Cl 638.2 6.9 I-205

H 591.2 7.0 I-206

H 591.2 7.0 I-207

H 591.3 6.8 I-208

H 591.2 6.8 I-209

H 642.3 7.3 I-210

H 644.3 7.2 I-211

H 642.3 5.7 I-212

H 644.3 6.3 I-213

H 602.1 5.3 I-214

H 602.2 5.6 I-215

H 604.2 5.5

Example I-216 was prepared following the procedures described in step10D, by replacing but-3-enoic acid with 3-methyl-4-pentenoic; followedby steps 2E; 10H; and 15D, by replacing Intermediate 2 with2,6-difluoro-4-methylbenzoic acid. Example I-217 was prepared followingthe procedures described in step 10D, by replacing but-3-enoic acid with3-methyl-4-pentenoic; followed by steps 2E/2F; 10G; 10H; and 15D, byreplacing Intermediate 2 with 2,6-difluoro-4-methylbenzoic acid.Examples I-218 to I-219 were prepared following the procedures describedin step 10D, by replacing but-3-enoic acid with 3-ethyl pent-4-enoicacid; followed by steps 2E/2F; 10H; and 15D, by replacing Intermediate 2with 2,6-difluoro-4-methylbenzoic acid. Examples I-220 and I-221 wereprepared following the procedures described in step 10D, by replacingbut-3-enoic acid with 2-methyl-4-pentenoic acid; followed by steps2E/2F; 10H; and 15D, by replacing Intermediate 2 with2,6-difluoro-4-methylbenzoic acid.

TABLE I-12 Examples I-216 to I-221

HPLC Ex. LCMS RT # L—Y R³ [M + H]⁺ (min) 216

Cl 558.1 7.5 217

Cl 560.0 7.1 218

H 538.2 4.9 219

H 538.2 4.9 220

H 524.3 5.1 221

H 524.2 5.0

EXAMPLE I-226(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-((E)-(S)-4-fluoro-9-oxo-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,12,16(19)-hexaen-15-yl)-acrylamide,trifluoroacetic acid salt

I-226A. 2-Methyl-propane-2-sulfinic acid{(S)-1-[4-(5-fluoro-2-nitro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-but-3-enyl}-amide:A microwave vial containing a mixture of Intermediate 37 (409.6 mg,0.909 mmol), 5-fluoro-2-nitrophenylboronic acid (336 mg, 1.818 mmol) andpotassium carbonate (251 mg, 1.818 mmol) in dioxane (5.82 mL) and water(1.46 mL) was degassed with argon for 5 min. Next,bis(tri-t-butylphosphine)palladium (0) (23.23 mg, 0.045 mmol) was addedand the vial was sealed and heated in a microwave to 130° C. for 10 min.Additional 5-fluoro-2-nitrophenylboronic acid (1 eq) and potassiumcarbonate (1 eq) was added to the vial and the vial was degassed withargon for 5 min. Additional bis(tri-t-butylphosphine)palladium (0)(23.23 mg, 0.045 mmol) was added and the vial was sealed and heated in amicrowave at 130° C. for 10 min. Additional5-fluoro-2-nitrophenylboronic acid (1 eq) and potassium carbonate (1 eq)was added to the vial and the vial was degassed with argon for 5 min.Additional bis(tri-t-butylphosphine)palladium (0) (23.23 mg, 0.045 mmol)was added and the vial was sealed and heated in a microwave at 130° C.for 10 min. The reaction was partitioned between water and ethyl acetateand the layers were separated. The aqueous layer was extracted withEtOAc (2×). The combined organic layers were washed with sat.NaHCO₃(aq), brine, dried over Na₂SO₄, filtered and concentrated to athick brown oil. Purification by normal phase chromatography gave 168.4mg (36.3%) of I-226A as a yellow oil. MS (ESI) m/z: 511.2 (M+H)⁺.

I-226B.{(S)-1-[4-(5-Fluoro-2-nitro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-but-3-enyl}-carbamicacid tert-butyl ester: To a dark yellow solution of I-226A (314.6 mg,0.616 mmol) in MeOH (6.16 mL) was added dropwise 4M HCl in dioxane (0.77mL, 3.08 mmol). The reaction was allowed to stir at RT. After 30 min,the reaction was quenched with the dropwise addition of sat. NaHCO₃(aq)and then it was concentrated to give a light brown oil. The oil was thenpartitioned between sat. NaHCO₃(aq) and DCM and the layers wereseparated. The aqueous layer was extracted with DCM (1×). The organiclayers were combined, washed with brine, dried over MgSO₄, filtered andconcentrated to give 204.7 mg (82%) of the amine as an orange oil. MS(ESI) m/z: 407.1 (M+H)⁺.

To a solution of amine (196.9 mg, 0.444 mmol) in DCM (1.4 mL) was addedtriethylamine (0.248 mL, 1.778 mmol). Next, BOC₂O (0.114 mL, 0.489 mmol)was added. After 30 min, the reaction was partitioned between DCM andsat. NaHCO₃(aq) and the layers were separated. The aqueous layer wasextracted with DCM. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to an orange oil.Purification by normal phase chromatography gave 195.7 mg (87%) ofI-226B as a yellow-green residue. MS (ESI) m/z: 507.3 (M+H)⁺.

I-226C. Example I-226 was prepared following the procedures described in15B, by replacing 15A with 1-226B; followed by steps 10D, by replacingbut-3-enoic acid with pent-4-enoic acid; 2E/2F; 10H; and 15D. MS (ESI)m/z: 533.1 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ: 2.33-2.51 (m, 4 H),2.53-2.61 (m, 1 H), 2.77-2.86 (m, 1 H), 5.09 (dd, J=9.9, 4.7 Hz, 1 H),5.37-5.46 (m, 1 H), 5.52-5.60 (m, 1 H), 6.76 (d, J=15.7 Hz, 1 H), 7.15(d, J=15.7 Hz, 1 H), 7.27-7.38 (m, 3 H), 7.49 (s, 1 H), 7.59 (d, J=8.5Hz, 1 H), 7.68 (dd, J=8.5, 2.2 Hz, 1 H), 7.98 (d, J=2.5 Hz, 1 H), 9.51(s, 1 H).

TABLE I-13 Examples I-222 to I-230 HPLC Ex. LCMS RT # Structure [M + H]⁺(min) I-222

548.1 6.9 I-223

576.2 5.4 I-224

577.2 4.3 I-225

563.2 4.1 I-226

533.1 5.2 I-227

567.0 7.5 I-228

516.1 5.4 I-229

592.0 7.6

EXAMPLES I-241 and I-242(9S,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acrylamino]-5-methoxycarbonylamino-17-methyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid ethyl ester, bis-trifluoroacetic acid salt, and(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-methoxycarbonylamino-17-methyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid ethyl ester, bis-trifluoroacetic acid salt

These compounds were prepared using a variation of the proceduresemployed to make compounds I-67 and I-68.

I-241A.[4-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-(2,2,2-trifluoro-acetylamino)-phenyl]-carbamicacid methyl ester: To a suspension of Example 10C (3 g, 5.64 mmol) inCH₂Cl₂ (40 ml) at 0° C. was added Et₃N (0.944 ml, 6.77 mmol), followedby (CF₃CO)₂O (0.797 ml, 5.64 mmol). The solvent was removed in vacuo andthe residue was purified by normal phase chromatography to give to givea yellow foam (3.0 g, 4.54 mmol, 80% yield): MS (ESI) m/z: 628.5.

I-241B.[4-[5-Bromo-2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-(2,2,2-trifluoro-acetylamino)-phenyl]-carbamicacid methyl ester: To a solution of Example I-241A (1.0 g, 1.593 mmol)in CHCl₃ (10 mL) at 0° C. was added 1-bromopyrrolidine-2,5-dione (0.284g, 1.593 mmol) and stirred at the same temperature for 10 min. Thereaction mixture was concentrated in vacuo and purified by normal phasechromatography: MS (ESI) m/z: 708.

I-241C.[4-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-(2,2,2-trifluoro-acetylamino)-phenyl]-carbamicacid methyl ester: To a mixture of Example I-241C (200 mg, 0.283 mmol),methylboronic acid (85 mg, 1.415 mmol) and K₃PO₄ (148 mg, 0.849 mmol) ina microwave vial was added dioxane (5 mL), which had been degassed bybubbling argon through it for 30 min. The reaction mixture was againdegassed for 15 mins. To this mixture was then added PdCl₂(dppf)-CH₂Cl₂adduct (46.2 mg, 0.057 mmol) and sealed immediately and subjected tomicrowave heating for 25 mins at 150° C. The reaction mixture wasdiluted with EtOAc and washed with brine. Drying over Na₂SO₄,filtration, removal of solvent in vacuo and purification of the residueby normal phase chromatography gave an oil: MS (ESI) m/z=642.3.

I-241D.{3-Amino-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: To a solution of I-241C (420 mg, 0.654 mmol) in MeOH(5 mL) was added a solution of LiOH (7 mL, 7 mmol) and stirred at 60° C.for 1.5 h. The reaction mixture was acidified to pH 6 with 1N HCl andextracted with EtOAc three times. The combined organic layers were driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by normal phase chromatography to give an oil. MS (ESI) m/z:546.3.

Examples I-241 and I-242. The synthesis followed the procedures for I-67and I-68 using Example I-241D instead of Example 10C. This gave rise toethyl ester diastereomers instead of methyl ester diastereomers. Eachdiastereomer was separately carried on through the rest of the sequenceas described for Examples I-67 and I-68.

For Example I-241: ¹H NMR (500 MHz, CD₃CN) δ 9.11 (s, 1H), 8.81 (d,J=6.1 Hz, 1H), 7.85-7.79 (m, 2H), 7.61 (dd, J=8.5, 2.5 Hz, 1H), 7.50 (d,J=8.5 Hz, 1H), 7.29 (d, J=2.2 Hz, 1H), 7.20-7.16 (m, 1H), 7.08 (dd,J=8.3, 2.2 Hz, 1H), 6.98 (d, J=15.4 Hz, 1H), 6.66 (d, J=15.7 Hz, 1H),5.33 (m, 1H), 4.09-3.94 (m, 2H), 3.70 (s, 3H), 3.07 (dd, J=9.8, 2.9 Hz,1H), 2.30-2.21 (m, 5H), 1.94 (m, 1H), 1.85 (br. s., 1H), 1.63-1.50 (m,2H), 1.45-1.31 (m, 2H), 1.11 (t, J=7.2 Hz, 4H), 0.75-0.65 (m, 1H).

For Example I-242, ¹H NMR (500 MHz, CD₃CN) δ: 10.02 (d, J=8.5 Hz, 1H),9.08 (s, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.66 (s, 1H), 7.60 (dd, J=8.5, 2.5Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.21-7.15 (m, 2H), 7.15-7.10 (m, 1H),6.79-6.72 (m, 1H), 6.63-6.58 (m, 1H), 5.84 (dt, J=10.9, 8.2 Hz, 1H),4.02-3.88 (m, 2H), 3.74-3.67 (m, 3H), 2.96 (d, J=11.3 Hz, 1H), 2.39-2.31(m, 4H), 2.17-2.02 (m, 2H), 1.94 (m, 1H), 1.76-1.63 (m, 2H), 1.56-1.44(m, 2H), 1.44-1.32 (m, 1H), 1.11-1.02 (m, 3H), 0.44-0.32 (m, 1H).

EXAMPLE I-243(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acrylamino]-5-methoxycarbonylamino-17-methyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid methyl ester, bis-trifluoroacetic acid salt

I-243A. (R)-Methyl2-(N-(2-(2-((S)-1-(tert-butoxycarbonylamino)but-3-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-5-(methoxycarbonylamino)phenyl)-2,2,2-trifluoroacetamido)pent-4-enoate:Example I-74B (3.66 g, 5.68 mmol) was dissolved in EtOAc (50 mL) and thereaction mixture was cooled to 0° C. Et₃N (1.585 ml, 11.37 mmol) wasadded followed by (CF₃CO)₂O (0.964 ml, 6.82 mmol). The reaction mixturewas allowed to warm to RT over 72h. The reaction mixture was dilutedwith water and extracted three times with EtOAc. The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by normal phasechromatography: Wt=500 mg; MS (ESI) m/z: 740.

I-243B.(E)-(9R,14S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-8-(2,2,2-trifluoro-acetyl)-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaene-9-carboxylicacid methyl ester: Example I-243A (500 mg, 0.676 mmol) was dissolved inDCE (15 ml) and reacted with Grubbs II catalyst according to theprocedure described for I-74C. Workup and purification by normal phasechromatography provided a solid (Wt=730 mg): MS (ESI) m/z: 712.5.

I-243C.(9R,14S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-8-(2,2,2-trifluoro-acetyl)-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid methyl ester: Example I-243C was prepared according to theprocedure described for I-74D using precursor I-243B (730 mg). Workupand normal phase chromatography provided the desired intermediate(Wt=520 mg): MS (ESI) m/z: 714.

I-243D.(9R,14S)-17-Bromo-14-tert-butoxycarbonylamino-5-methoxycarbonylamino-8-(2,2,2-trifluoro-acetyl)-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid methyl ester: Example I-243C (520 mg, 0.628 mmol) was dissolved inCHCl₃ (10 mL). Reaction mixture cooled to 0° C. and NBS (123 mg, 0.691mmol) was added. The reaction was allowed to stir at 0° C. The reactionmixture was concentrated in vacuo and the residue was purified by normalphase chromatography. (Wt=225 mg): MS (ESI) m/z: 795, 793. ¹H NMR (500MHz, MeOH-d3) δ ppm 9.57 (1 H, br. s.), 7.83-7.95 (1 H, m), 7.60 (1 H,dd, J=8.25, 1.65 Hz), 7.39 (1 H, d, J=8.25 Hz), 5.75 (1 H, d, J=11.55Hz), 5.42 (1 H, d, J=11.00 Hz), 4.97-5.02 (1 H, m), 4.48-4.62 (1 H, m),3.80 (3 H, s), 3.78 (3 H, s), 3.58-3.71 (1 H, m), 2.22-2.36 (1 H, m),1.84-1.97 (1 H, m), 1.64-1.81 (2 H, m), 1.44 (9 H, s), 0.84-1.05 (3 H,m), 0.00 (9 H, s).

I-243E.(9R,14S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-17-methyl-8-(2,2,2-trifluoro-acetyl)-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid methyl ester:

To a mixture of Example I-243D (78 mg, 0.098 mmol), methylboronic acid(10.57 mg, 0.177 mmol) and K₃PO₄ (18.46 mg, 0.106 mmol) in a microwavevial was added dioxane (1 mL) which was degassed by bubbling argonthrough it for 30 min. The reaction mixture was again degassed for 15mins. To this mixture was then added PdCl₂(dppf)-CH₂Cl₂ adduct (5.77 mg,7.06 μmol) and the reaction vial was sealed immediately and subjected tomicrowave heating for 15 min at 150° C. The reaction mixture was dilutedwith ethyl acetate and washed with brine. The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated in vacuo. Normalphase chromatography provided a solid (Wt=33 mg): MS (ESI) m/z: 696.4.

I-243F.(9R,14S)-14-Amino-5-methoxycarbonylamino-17-methyl-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid methyl ester, di-hydrochloride salt: Example I-243F was preparedfrom Example I-243E (42.7 mg, 0.227 mmol) using the procedure describedfor Example I-61B. Workup and reverse phase chromatography provided asolid which was a trifluoroacetic acid salt (Wt=11 mg): MS (ESI) m/z:402.3.

Example I-243. Example I-243F (11 mg, 0.015) and(E)-2,5-dioxopyrrolidin-1-yl3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylate (5.2 mg, 0.015 mmol)were reacted according to the procedure for Example 1G. Workup andreverse phase chromatography gave the desired product as abis-trifluoroacetic acid salt (Wt=6 mg): MS (ESI) m/z: 634.4. ¹H NMR(500 MHz, CD₃CN) δ 9.91 (d, J=8.3 Hz, 1H), 9.08 (s, 1H), 7.83 (d, J=2.2Hz, 1H), 7.74-7.42 (m, 3H), 7.26-7.06 (m, 3H), 6.77 (d, J=15.7 Hz, 1H),6.65-6.57 (m, 1H), 5.80 (dt, J=11.3, 7.8 Hz, 1H), 3.76-3.65 (m, 3H),3.55-3.46 (m, 3H), 3.01 (d, J=11.6 Hz, 1H), 2.39-2.31 (m, 3H), 2.19-2.02(m, 2H), 1.94 (m, 2H) 1.77-1.62 (m, 2H), 1.56-1.32 (m, 3H), 0.46-0.29(m, 1H).

EXAMPLE I-244(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-17-cyclopropyl-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid methyl ester, bis-trifluoroacetic acid salt

The synthesis for this compound followed the procedure for Example I-243using cyclopropylboronic acid instead of methyl boronic acid in the stepto make Example I-243E. Example I-244 was isolated as abis-trifluoroacetic acid salt. MS (ESI) m/z: 660.3; ¹H NMR (500 MHz,CD₃CN) δ 10.36 (d, J=8.8 Hz, 1H), 9.08 (s, 1H), 7.80 (d, J=2.2 Hz, 1H),7.65-7.54 (m, 2H), 7.46 (d, J=8.8 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H),7.18-6.98 (m, 2H), 6.63-6.56 (m, 2H), 5.97-5.86 (m, 1H), 3.71 (s, 3H),3.48 (s, 3H), 2.87 (d, J=11.5 Hz, 1H), 2.14-2.02 (m, 2H), 1.75-1.42 (m,6H), 1.34 (t, J=13.2 Hz, 2H), 1.08-0.98 (m, 1H), 0.94-0.77 (m, 3H),0.32-0.16 (m, 1H).

EXAMPLE I-245{(S)-17-Carbamoyl-14-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA

I-115D (0.050 g, 0.073 mmol) was dissolved in DMSO (0.367 ml) and K₂CO₃(0.030 g, 0.220 mmol) was added followed by dropwise addition of 30%hydrogen peroxide (0.083 ml, 0.808 mmol). A thick white precipitateformed. The reaction was stirred at room temperature for 5.5 h under Ar.Reaction mixture was diluted with EtOAc and washed with water (3×) andbrine, then dried over MgSO₄, filtered, and evaporated to yield amixture of product, partially deprotected product (loss oftrifluoroacetamide) and SM. This mixture was purified by reverse phaseHPLC to remove the unreacted SM, and the product mixture was fullydeprotected using the procedure described for step I-61B, followed bycoupling of the resulting amine with Intermediate 1 using the proceduredescribed in step 1G to yield Example I-245 as a white solid. ¹H NMR(500 MHz, CD₃OD) δ ppm 9.71 (1 H, s) 9.55 (1 H, s) 7.94 (1 H, d, J=1.65Hz) 7.89 (1 H, d, J=8.25 Hz) 7.86 (1 H, br. s.) 7.61-7.67 (1 H, m)7.55-7.60 (1 H, m) 7.26 (1 H, dd, J=8.52, 1.92 Hz) 7.23 (1 H, d, J=15.40Hz) 6.79 (1 H, d, J=15.40 Hz) 5.15 (1 H, dd, J=10.45, 6.60 Hz) 3.73 (3H, s) 3.20 (1 H, d, J=12.65 Hz) 2.97 (1 H, t, J=12.65 Hz) 2.09-2.18 (1H, m) 2.00 (1 H, t, J=11.27 Hz) 1.79-1.92 (2 H, m) 1.61 (2 H, t, J=13.75Hz) 1.32 (1 H, br. s.) 0.62 (1 H, d, J=12.65 Hz). MS (ESI) m/z: 605.4(M+H)⁺. Analytical HPLC: RT=4.98 min.

EXAMPLE I-246(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-17-carboxylicacid methyl ester, 2TFA

I-115D (0.025 g, 0.037 mmol) was dissolved in MeOH (0.5 ml), and thenconcentrated H₂SO₄ (0.050 ml) was added at rt. The reaction was heatedat 75° C. under Ar overnight at which point the desired product,(S)-14-amino-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-17-carboxylicacid methyl ester (I-246A) was obtained along with(S)-5,14-diamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-17-carboxylicacid methyl ester (I-246B) from cleavage of the methylcarbamate. Thereaction mixture was cooled to rt and diluted with MeOH, then filteredand purified by reverse phase HPLC. I-246A was deprotected using theprocedure described in step I-61B, and the resulting amine coupled withIntermediate 1 using the procedure described for step 1G to provideExample I-246. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.28 (1 H, br. s.) 10.76(1 H, br. s.) 10.18 (1 H, br. s.) 9.86 (1 H, s) 8.43 (1 H, d, J=5.50 Hz)8.03 (1 H, d, J=7.15 Hz) 7.99 (1 H, d, J=2.20 Hz) 7.95 (1 H, br. s.)7.69-7.79 (2 H, m) 7.44 (1 H, d, J=7.70 Hz) 6.84-6.93 (2 H, m) 5.19-5.28(1 H, m) 3.80 (3 H, s) 3.72 (3 H, s) 3.05 (1 H, d, J=11.00 Hz) 2.83 (1H,t, J=11.28 Hz) 1.91-2.00 (1 H, m) 1.79 (2 H, br. s.) 1.66 (1 H, q,J=10.73 Hz) 1.36-1.49 (2 H, m) 1.17 (1 H, br. s.) 0.61 (1 H, d, J=13.75Hz). MS (ESI) m/z: 620.4 (M+H)⁺. Analytical HPLC: RT=5.55 min.

EXAMPLE I-247(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acrylamino]-17-cyano-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid methyl ester, 2TFA

I-247A. (R)-Methyl2-(N-(2-(2-((S)-1-(tert-butoxycarbonylamino)but-3-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-5-(methoxycarbonylamino)phenyl)-2,2,2-trifluoroacetamido)pent-4-enoate:I-74B (12 g, 13.98 mmol) was dissolved in ethyl acetate (100 ml).Pyridine (1.357 ml, 16.77 mmol) was added, and the reaction was cooledto 0° C. TFAA (2.172 ml, 15.38 mmol) was added dropwise with stirring,and reaction allowed to reach RT, then stirred at room temperature underAr overnight. Reaction was diluted with EtOAc and water. Aq. phase wasextracted 3× with EtOAc, and the combined organic phases were dried withsodium sulfate, filtered and concentrated. Residue was purified by flashchromatography to provide the desired trifluoroacetamide containingminor impurities which do not separate on silica gel. This crude productwas taken on without further purification.

I-247B.(9R,14S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-8-(2,2,2-trifluoroacetyl)-16-(2-trimethylsilanylethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid methyl ester: I-247A (6.15 g, 8.31 mmol) was dissolved in DCE (208ml) in a rbf equipped with an argon inlet and reflux condenser. Thesolution was degassed by bubbling with Ar for 15 minutes. The reactionmixture was heated to 84° C., and a solution of Grubbs II (1.059 g,1.247 mmol) dissolved in 15 mL of DCE was added. Reaction mixture wasstirred at 84° C. under Ar for 15 hours. Reaction was quenched byaddition of a saturated NaHCO₃ solution and diluted with DCM. Theorganic layer was extracted one more time with saturated NaHCO₃ solutionand once with brine. Organic phase was dried with Na₂SO₄, filtered andconcentrated. Residue was purified by flash chromatography to providethe RCM product in ˜37% yield as a mixture of cis/trans isomers. Aportion of this intermediate (1.9 g, 2.67 mmol) was taken up in MeOH(26.7 ml) and Pd/C (0.284 g, 0.267 mmol) added. The mixture was thenstirred at room temperature under 50 psi H₂ for 48 h to provide I-127-B(1.66g, 87%) after removal of catalyst and evaporation of solvent. MS(ESI) m/z: 714.3 (M+H)⁺.

I-247C.(9R,14S)-14-tert-Butoxycarbonylamino-17-cyano-5-methoxycarbonylamino-8-(2,2,2-trifluoro-acetyl)-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylic acid methyl ester:(9R,14S)-17-Bromo-14-tert-butoxycarbonylamino-5-methoxycarbonylamino-8-(2,2,2-trifluoro-acetyl)-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylic acid methyl ester, prepared fromI-247B using the procedure described for I-115C, (2.0 g, 2.52 mmol) wasdissolved in DMF (12.61 ml). Zinc cyanide (0.178 g, 1.514 mmol) wasadded and the reaction was degassed by bubbling with Ar for 15 minutes.(Ph₃)₄Pd (0.292 g, 0.252 mmol) was added and the mixture stirred at 120°C. for 10 hours under Ar. Reaction mixture was diluted with EtOAc,washed 4× with 10% LiCl, brine, dried with sodium sulfate, filtered andconcentrated. Residue was purified by flash chromatography to provide1.44 g of a 3:1 mixture cyano product to starting bromide. This mixturewas re-subjected to the above reaction conditions and isolation to yieldI-247C in ˜60% yield after chromatography. MS (ESI) m/z: 739.3 (M+H)⁺.

I-247D.(9R,14S)-14-Amino-17-cyano-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylic acid methyl ester, 3TFA: I-247C(0.106 g, 0.143 mmol) was dissolved in MeOH (2 mL) and a solution ofO-methylhydroxylamine in H₂O (25% w/w, 0.135 mL, 0.717 mmol) was addedfollowed by 6M HCl (2 mL). The mixture was heated with stirring in asealed tube at 75° C. ON. Reaction mixture was concentrated, andHCl/Dioxane (0.5 mL) and MeOH (2 mL) were added followed by stirringovernight at room temperature. The mixture was concentrated and residuepurified by reverse phase HPLC to provide I-247D (0.031 g, 28.6%) as awhite solid. MS (ESI) m/z: 413.3 (M+H)⁺.

I-247E. Example I-247 was prepared from I-247D by coupling withIntermediate 1 using the procedure described for step 1G. ¹H NMR (500MHz, CD₃OD) δ ppm 9.50 (1 H, br. s.), 8.00 (1 H, d, J=2.20 Hz), 7.65 (1H, dd, J=8.80, 2.20 Hz), 7.56 (1 H, d, J=8.80 Hz), 7.46 (1 H, d, J=8.25Hz), 7.42-7.45 (1 H, m), 7.16 (1 H, dd, J=8.52, 1.92 Hz), 7.10 (1 H, d,J=15.40 Hz), 6.80 (1 H, d, J=15.95 Hz), 5.19 (1 H, dd, J=10.72, 6.87Hz), 3.74 (3 H, s), 3.58 (3 H, s), 3.01-3.07 (1 H, m), 2.05-2.17 (1 H,m), 1.80-1.92 (2 H, m), 1.69-1.80 (1 H, m), 1.32-1.53 (4 H, m),0.33-0.51 (1 H, m). MS (ESI) m/z: 645.4 (M+H)⁺. Analytical HPLC: RT=8.23min.

EXAMPLE I-248(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9,17-dicarboxylicacid dimethyl ester, 2TFA

I-248A.(9R,14S)-14-tert-Butoxycarbonylamino-17-carbamoyl-5-methoxycarbonylamino-8-(2,2,2-trifluoroacetyl)-16-(2-trimethylsilanylethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylic acid methyl ester: I-247C (60mg, 0.081 mmol), acetaldehyde oxime (9.90 μl, 0.162 mmol),triphenylphosphine (4.26 mg, 0.016 mmol) and palladium(II) acetate(1.823 mg, 8.12 μmol) were weighed into a 1 dram pressure-rated vial,and ethanol (0.2 mL) and water (0.050 mL) were added. The vial wasflushed with argon and capped, and the reaction mixture was heated at80° C. with stirring for ˜1 h. Reaction was cooled to room temperature,filtered through a syringe filter, which was further washed with mix ofMeOH/CH₂Cl₂, and the filtrate was stripped to dryness. Residue waspurified by flash chromatography to provide I-248A (42.1 mg, 68.5%). MS(ESI) m/z: 757.4 (M+H)⁺

I-248B.(9R,14S)-14-Amino-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9,17-dicarboxylic acid dimethyl ester, 3TFA: I-248B wasobtained from I-248A using the procedure described for step I-61B andisolated as the tris-TFA salt after reverse phase HPLC.

I-248C. Example I-248 was prepared from I-248B by coupling withIntermediate 1 using the procedure described for step 1G. ¹H NMR (500MHz, CD₃OD) δ ppm 9.50 (1 H, s), 7.98 (1 H, d, J=2.2 Hz), 7.67 (1 H, dd,J=8.8, 2.2 Hz), 7.59 (1 H, s), 7.57 (1 H, s), 7.45 (1 H, s), 7.09-7.16(2 H, m), 6.76 (1 H, d, J=15.4 Hz), 5.18 (1 H, dd, J=11.0, 7.1 Hz), 3.88(3 H, s), 3.75 (3 H, s), 3.59 (3 H, s), 3.05 (1 H, d, J=11.5 Hz),2.21-2.33 (1 H, m), 1.99-2.08 (1 H, m), 1.67-1.78 (2 H, m), 1.51-1.62 (1H, m), 1.37-1.50 (2 H, m), 0.40-0.55 (1 H, m). MS (ESI) m/z: 678.1(M+H)⁺. Analytical HPLC: RT=6.52 min.

EXAMPLE I-250(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acrylamino]-17-cyano-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid, 2 TFA

I-250A.(9R,14S)-14-Amino-17-cyano-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid, 3 TFA: A mixture of I-247C (165 mg, 0.193 mmol), O-methoxyaminehydrochloride (30% in water, 0.245 mL, 0.967 mmol), 6M HCl (1.29 ml,7.74 mmol) and MeOH (1.6 ml) was heated with stirring in a 75° C. oilbath overnight in a sealed 5 mL pressure-rated vial. Reaction was cooledto room temperature and determined by LCMS to be an ˜1:1 mixture ofmethyl ester and acid products. The mixture was stripped to dryness, andresidue was redissolved in a mixture of 4 mL THF, 2.5 mL 1M LiOH and˜0.5 mL MeOH, then stirred overnight at room temperature under nitrogen.Reaction mixture was neutralized with 1M HCl and stripped to dryness.Residue was purified by reverse phase HPLC to provide I-250A (29.3 mg,29.6%) and the corresponding methyl ester, I-247D (23.2 mg, 22.78%).I-250A MS (ESI) m/z: 399.2 (M+H)⁺.

I-250B. Example I-250 was prepared from I-250A by coupling withIntermediate 1 using the procedure described for step 1G. ¹H NMR (500MHz, DMSO-d₆) δ ppm 12.98 (1 H, br. s.), 9.86 (1 H, s), 9.79 (1 H, s),8.76 (1 H, d, J=7.7 Hz), 7.93 (1 H, d, J=2.2 Hz), 7.67-7.80 (2 H, m),7.34 (1 H, br. s.), 7.28 (1 H, d, J=8.2 Hz), 7.10 (1 H, d, J=8.2 Hz),6.82-6.96 (2 H, m), 5.14-5.27 (1 H, m), 5.00 (1 H, br. s.), 3.67 (3 H,s), 2.68-2.85 (1 H, m), 1.99 (1 H, br. s.), 1.59-1.79 (3 H, m),1.17-1.36 (3 H, m), 0.33 (1 H, br. s.). MS (ESI) m/z: 631.4 (M+H)⁺Analytical HPLC: RT=7.66 min.

EXAMPLE I-251(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acrylamino]-17-cyano-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid ethyl ester, 2 TFA

Example I-251. Example I-250 (15.8 mg, 0.018 mmol) was dissolved in EtOH(0.5 ml) and TMS-Cl (5.64 μl, 0.044 mmol) was added under nitrogen.Reaction mixture was stirred at room temperature overnight. Only a smallamount of desired product was observed, therefore, the solution wastransferred to a pressure-rated vial using ˜0.2 mL additional EtOH torinse. An additional 20 μL TMS-Cl were added, and the vial was cappedand heated with stirring at 75° C. for 4 h. LCMS shows completeconversion to ethyl ester. Reaction mixture was stripped to dryness andcrude product was redissolved in MeOH, filtered and purified by reversephase HPLC to provide Example I-251 (6.8 mg, 40.4%) as a white solid. ¹HNMR (500 MHz, CD₃CN) δ ppm 9.10 (1 H, s), 7.88 (1 H, d, J=2.2 Hz), 7.86(1 H, s), 7.61 (1 H, dd, J=8.5, 2.2 Hz), 7.52 (2 H, dd, J=11.8, 8.5 Hz),7.41 (1 H, d, J=1.9 Hz), 7.36 (1 H, d, J=7.4 Hz), 7.17 (1 H, dd, J=8.3,2.2 Hz), 7.01 (1 H, d, J=15.4 Hz), 6.65 (1 H, d, J=15.7 Hz), 5.30 (1 H,ddd, J=10.9, 7.0, 6.9 Hz), 3.92-4.07 (2 H, m), 3.71 (3 H, s), 2.94-3.05(1 H, m), 2.05-2.16 (1 H, m), 1.66-1.83(3 H, m), 1.32-1.57(3 H, m), 1.10(3 H, t, J=7.2 Hz), 0.42 (1 H, d, J=12.7 Hz). MS (ESI) m/z: 659.2(M+H)⁺. Analytical HPLC: RT=9.00 min.

TABLE I-14 Examples I-231 to I-251

HPLC Ex. LCMS RT # R7 R3 [M + H]⁺ (min.) I-231 CH₂OMe H 606.3 9.1(homochiral) I-232 CH₂OMe H 606.3 9.0 (homochiral) I-233

H 659.3 5.9 I-234

H 661.2 5.8 I-235

H 659.2 5.8 I-236

H 645.3 5.1 I-237

H 675.3 5.1 I-238

H 635.2 5.4 I-239

H 634.2 6.8 I-240

H 620.1 5.3 I-241

Me 648.4 6.1 I-242

Me 648.4 5.9 I-243

Me 634.4 5.8 I-244

660.3 6.2 I-245 H CONH₂ 605.4 5.0 I-246 H CO₂Me 620.4 5.5 I-247

CN 645.4 8.2 I-248

CO₂Me 678.3 6.1 I-249

CN 658.4 7.8 I-250

CN 631.4 7.7 I-251

CN 659.2 9.0

EXAMPLE I-252(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-methoxycarbonylamino-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylic acid tert-butyl ester,trifluoroacetic acid salt

I-252A.3-{2-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-5-methoxycarbonylamino-phenyl}-propionicacid tert-butyl ester: (Molander, G. A., Organic Letters, 10(9):1795(2008).) A thick-walled 150-mL screw top flask containing potassium3-trifluoroboratopropionate tert-butyl ester (2.180 g, 9.23 mmol), 10B(5.0 g, 8.39 mmol), palladium acetate (0.141 g, 0.630 mmol),2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (Ru-Phos)(0.588 g, 1.259 mmol), and potassium carbonate (3.48 g, 25.2 mmol) waspurged with argon for several minutes. Next, degassed toluene (33.6 ml)and degassed water (8.4 ml) were added and under a blanket of argon theseptum was replaced with a teflon screw cap possessing a Viton O-ring.The biphasic orange mixture was warmed to 85° C. After 24 h, thereaction was stopped and cooled to RT. The layers were separated and theaqueous layer was extracted with EtOAc (2×). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated togive a yellow foam weighing 6.63 g. Purification by normal phasechromatography (gradient elution 0-20% EtOAc/DCM) gave 1.45 g (27%) ofI-252A, as a white foam. MS (ESI) m/z: 645.4 (M+H)⁺.

I-252B.2-{2-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-5-methoxycarbonylamino-benzyl}-pent-4-enoicacid tert-butyl ester: To a cooled solution (−78° C.) ofdiisopropylamine (1.167 ml, 8.19 mmol) in degassed THF (14 mL) was addeddropwise n-BuLi (4.65 ml, 7.44 mmol). The resulting clear, pale yellowsolution was stirred at −78° C. for 45 min. Next, a clear, pale yellowsolution of I-252A (1.20 g, 1.86 mmol) in THF (degassed, 9 ml) was addeddropwise over 30 min. The resulting yellow suspension was stirredvigorously at −78° C. After 1.5 h, allyl bromide (0.161 ml, 1.861 mmol)was added dropwise. The reaction mixture was stirred at −78° C. After 1h, the clear, pale yellow solution was allowed to slowly warm to −15° C.The reaction was quenched with the dropwise addition of sat. ammoniumchloride and the reaction was allowed to warm to RT. The reaction waspartitioned between water and EtOAc and the layers were separated. Theaqueous layer was extracted with EtOAc (2×). The combined organic layerswere washed with sat. NaHCO₃, brine, dried over Na₂SO₄, filtered andconcentrated to give a yellow foam. Purification by normal phasechromatography (gradient elution 0-20% EtOAc/DCM) gave 1.04 g (70%) as a1:2.6 mixture of I-252A:I-252B. Compound I-252B is a mixture ofdiastereomers. MS (ESI) m/z: 686.7 (M+H)⁺.

I-252C.(S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-16-(2-trimethylsilanyl-ethoxymethyl)-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid tert-butyl ester, trifluoroacetic acid salt (Diastereomer A) andI-252D.(S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-16-(2-trimethylsilanyl-ethoxymethyl)-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid tert-butyl ester, trifluoroacetic acid salt (Diastereomer B). Thetitle compounds I-252C (Diastereomer A) and I-252D (Diastereomer B) wereprepared by following the procedures described in 2E/2F, by replacing 2Dwith the 1:2.6 mixture of I-253A:I-253B; followed by step 2G, byreplacing methanol with ethanol. The diastereomers were separated byreverse phase chromatography.

I-252E. Example I-252 was prepared by following the procedures describedin step 10H, by replacing 10G with 1-252C (diastereomer A) and byrunning the reaction at 75° C.; followed by step 1G. ¹H NMR (500 MHz,CD₃OD) δ0° C., δ ppm 9.46 (s, 1 H), 7.94 (d, J=2.2 Hz, 1 H), 7.68 (dd,J=8.8, 2.2 Hz, 1 H), 7.57 (d, J=8.8 Hz, 1 H), 7.45-7.52 (m, 3 H), 7.38(d, J=8.2 Hz, 1 H), 7.17 (d, J=15.9 Hz, 1 H), 6.74 (d, J=15.9 Hz, 1 H),5.18 (t, J=6.0 Hz, 1 H), 3.74 (s, 3 H), 2.79-2.91 (m, 2 H), 2.18-2.27(m, 2 H), 1.97-2.06 (m, 1 H), 1.30-1.67 (m, 4 H), 1.05-1.16 (m, 1 H),0.40-0.55 (m, 1 H). MS (ESI) m/z: 605.3 (M+H)⁺. Analytical HPLC: RT=8.82min.

Examples I-253 to I-255 were prepared from I-252C (diastereomer A)according to the procedures described in the previous examples. ExamplesI-256 to I-259 were prepared from I-252D (diastereomer B) according tothe procedures described in the previous examples.

TABLE I-15 Examples I-252 to I-259

HPLC Ex. LCMS RT # R7 R3 [M + H]⁺ (min.) I-252 CO₂H H 605.3 8.8(homochiral) I-253 CO₂Me H 619.4 9.2 (homochiral) I-254 CONMe₂ H 632.58.7 (homochiral) I-255 CONMe₂ Cl 666.2 7.4 (homochiral) I-256 CO₂H H605.3 8.8 (homochiral) I-257 CONHMe H 618.5 8.6 (homochiral) I-258CONMe₂ H 632.5 8.7 (homochiral) I-259 CONH₂ H 604.4 8.5 (homochiral)

TABLE I-16 Examples I-260 to I-264

LCMS HPLC Ex. # R R7 R3 [M + H]⁺ RT (min.) I-260

H H 556.3 8.1 I-261

H H 483.4 6.5 (C) I-262

H H 499.3 3.1 I-263

H 566.3 8.0 I-264

Cl 600.3 7.5

EXAMPLE 266(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-(2-methoxy-ethoxycarbonylamino)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-17-carboxylicacid methyl ester, 2TFA

Example I-266 was prepared from aniline, I-246B following a similarprocedure to that described for step I-123B. ¹H NMR (500 MHz, CD₃OD) δppm 9.53 (1 H, s) 8.34 (1 H, d, J=8.80 Hz) 8.03 (1 H, br. s.) 8.02 (1 H,d, J=2.20 Hz) 7.67-7.71 (1 H, m) 7.59-7.62 (1 H, m) 7.31 (1 H, dt,J=8.80, 1.10 Hz) 7.19 (1 H, d, J=15.95 Hz) 6.80 (1 H, d, J=15.40 Hz)5.31 (1 H, dd, J=10.17, 6.32 Hz) 4.26-4.32 (2 H, m) 3.89 (3 H, s) 3.65(2 H, t, J=4.67 Hz) 3.39 (3 H, s) 3.18-3.24 (1 H, m) 2.98 (1 H, t,J=11.27 Hz) 2.09-2.19 (1 H, m) 1.99 (1 H, br. s.) 1.83-1.96 (2 H, m)1.67 (2 H, t, J=12.10 Hz) 1.31 (1 H, br. s.) 0.69-0.82 (1 H, m). MS(ESI) m/z: 664.4 (M+H)⁺. Analytical HPLC: RT=5.65 min.

EXAMPLE I-267(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-(2-methoxy-ethoxycarbonylamino)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid, 2 TFA

Example I-131 (13 mg, 0.015 mmol) was dissolved in 4M HCl/dioxane (2mL)/water (0.5 mL) and heated to 55° C. in a sealed vial for 1.5 h. thenat 45° C. for 9h. Reaction mixture was filtered and residue was purifiedby reverse phase HPLC to provide Example I-267 (4.41 mg, 32.7%) as ayellow solid. ¹H NMR (500 MHz, CD₃CN) δ ppm 9.43 (1 H, br. s.), 9.09 (1H, s), 7.73-7.89 (2 H, m), 7.60 (1 H, dd, J=8.25, 2.20 Hz), 7.47 (1 H,d, J=8.25 Hz), 7.39 (1 H, s), 7.21-7.29 (2 H, m), 7.09-7.18 (1 H, m),6.82-6.93 (1 H, m), 6.62 (1 H, d, J=15.95 Hz), 5.59-5.76 (1 H, m),4.13-4.31 (2 H, m), 3.58 (2 H, t, J=4.40 Hz), 3.33 (3 H, s), 3.26 (1 H,s), 3.01 (1 H, d, J=11.55 Hz), 2.08-2.18 (1 H, m), 1.97-2.08 (1 H, m),1.64-1.77(2 H, m), 1.35-1.55 (3 H, m), 0.21-0.37 (1 H, m). MS (ESI) m/z:650.4 (M+H)⁺. Analytical HPLC: RT=5.18 min.

EXAMPLE I-270{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9,9-difluoro-8-oxo-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, TFA salt

I-270A. 2,2-Difluoro-1-morpholinopent-4-en-1-one: To a solution of2,2-difluoropent-4-enoic acid (701 mg, 5.15 mmol) in dichloromethane (10mL) was added catalytic amount of DMF (0.05 ml, 0.646 mmol). Then thereaction mixture was cooled in ice bath. To the solution was addedoxalyl chloride (0.460 ml, 5.15 mmol) dropwise. The resulting solutionwas stirred for 2 hr at rt.

Reaction mixture was then cooled in ice bath, added TEA (1.436 ml, 10.30mmol) and morpholine (0.497 ml, 5.7 mmol). The resulting solution wasstirred for 1.5 h at rt. The reaction mixture was then diluted withEtOAc (30 ml) and washed with aq. NH₄Cl. Organic solution was dried overMgSO₄ and concentrated in vacuo, yielding oily residue, which waspurified on normal phase chromatography to provide 633 mg (3.1 mmol, 60%yield) of I-270A as light brown oil. MS (ESI) m/z: 206.1 (M+1)⁺.

I-270B.[4-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-(2,2-difluoro-pent-4-enoyl)-phenyl]-carbamicacid methyl ester: To a solution of 10B (0.145 g, 0.243 mmol) in THF (2mL) under N₂ was added BuLi 2.5M in hex (0.487 mL, 1.217 mmol) at −78°C. The resulting solution was stirred for 0.5h and to the solution wasadded I-270A in 3 ml of THF dropwise for 10 min. The reaction mixturewas allowed to warm up to RT. The reaction was then quenched by addingaq. NH₄Cl (2 mL). The reaction mixture was then diluted with EtOAc (30ml) and washed with aq. NH₄Cl (10 mL). Organic solution was dried overMgSO₄ and concentrated in vacuo, yielding oily residue, which waspurified on normal phase chromatography to yield I-270B. TFA to yieldI-270B. TFA (43 mg, 0.057 mmol, 23.6%).

I-270C.[(E)-(S)-9,9-Difluoro-5-methoxycarbonylamino-8-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl]-carbamicacid tert-butyl ester: Compound I-270C was prepared following theprocedure described step 2E/2F, by replacing 2D with I-270B. MS (ESI)m/z: 607.2 (M+1)⁺.

I-270D.[(S)-9,9-Difluoro-5-methoxycarbonylamino-8-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester: A solution of I-270C (14 mg, 0.023 mmol) and PtO₂(3 mg, 0.013 mmol) in EtOAc (5 mL) and MeOH (5 ml) was stirred under H₂(50 psi) for 14h. The reaction mixture was filtered and concentrated invacuo to provide I-270D (14 mg, 100%), which was subjected to thefollowing reaction without further purification. MS (ESI) m/z: 609.3(M+H)⁺.

I-270E. Example I-270 was prepared following the procedures described instep 10H, by replacing 10G with 1-270D; followed by step 1G. ¹⁹F NMR(376 MHz, acetonitrile-d₃) δ ppm −76.47 (2 F, br. s.). MS (ESI) m/z:611.2 (M+H)⁺. Analytical HPLC: RT=5.59 min.

EXAMPLE I-280[(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-17-cyano-9-(3-hydroxy-azetidine-1-carbonyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]-carbamicacid methyl ester, 2TFA

A mixture of Example I-250 (0.020 g, 0.023 mmol), azetidin-3-olhydrochloride (3.83 mg, 0.035 mmol), and BOP reagent (0.015 g, 0.035mmol) in DMF (0.5 mL), was treated with DIPEA (0.020 mL, 0.116 mmol) andthen stirred at room temperature under Ar overnight. Reaction wasevaporated to remove DMF, and the residue was purified by reverse phaseHPLC to provide Example I-280 (0.0196 g, 92%) as a white solid. ¹H NMR(500 MHz, CD₃OD) δ ppm 9.52 (1 H, s), 8.00 (1 H, d, J=2.2 Hz), 7.67 (1H, dd, J=8.8, 2.2 Hz), 7.55-7.61 (2 H, m), 7.40 (1 H, dd, J=17.9, 1.9Hz), 7.28-7.33 (1 H, m), 7.14 (1 H, dd, J=15.7, 1.4 Hz), 6.80 (1 H, d,J=15.9 Hz), 5.22 (1 H, dd, J=11.0, 6.6 Hz), 4.33-4.47 (1 H, m),4.04-4.12 (1 H, m), 3.79-4.06 (1 H, m), 3.59-3.67 (1 H, m), 3.38-3.62 (1H, m), 3.13-3.18 (1 H, m), 2.12-2.21 (1 H, m), 1.77-2.01 (3 H, m),1.45-1.56 (2 H, m), 1.31 (1 H, t, J=14.0 Hz), 0.42-0.55 (1 H, m). MS(ESI) m z: 686.1 (M+H)⁺. Analytical HPLC: RT=6.98 min.

EXAMPLE I-283(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-17-cyano-5-methoxycarbonylamino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaene-9-carboxylicacid tert-butyl ester

To a solution of Example I-250 (0.03 g, 0.048 mmol) in THF (0.5ml)/Dichloromethane (0.5 ml) at RT was added t-BuOH (0.500 ml) and asolution of (E)-tert-butyl N,N′-diisopropylcarbamimidate (0.048 g, 0.238mmol) dissolved in DCM (0.3 mL). Reaction was allowed to stir at RT ON.Reaction was concentrated and residue was purified by reverse phaseHPLC. The fractions containing the product were neutralized by passingthrough a PL-HCO₃ MP SPE cartridge prior to evaporating to dryness toyield Example I-283 (12 mg, 36.4%) as a white solid. ¹H NMR (500 MHz,CD₃OD) δ ppm 9.53 (1 H, s), 8.02 (1 H, d, J=2.48 Hz), 7.68 (1 H, dd,J=8.53, 2.20 Hz), 7.59 (1 H, d, J=8.53 Hz), 7.46 (2 H, d, J=8.25 Hz),7.05-7.18 (2 H, m), 6.83 (1 H, d, J=15.68 Hz), 5.22 (1 H, dd, J=10.73,6.88 Hz), 3.77 (3 H, s), 2.77-2.87 (1 H, m), 2.09-2.19 (1 H, m),1.78-1.96 (2 H, m), 1.64-1.78 (1 H, m), 1.40-1.53 (2 H, m), 1.28-1.40(10 H, m), 0.39-0.55 (1 H, m). MS (ESI) m/z: 687.2 (M+H)⁺. AnalyticalHPLC: RT=9.28 min.

Example I-284 was prepared according to the procedure described in 88C,by replacing 88B with Intermediate 37 and by replacing Intermediate 12with Intermediate 39; followed by steps I-226B; 10D, by replacingbut-3-enoic acid with pent-4-enoic acid; 2E/2F; 10H; and 1G. ExamplesI-286 was prepared according to the procedure described in 88C, byreplacing 88B with Intermediate 37 and by replacing Intermediate 12 withIntermediate 39; followed by steps I-226B; 10D, by replacing but-3-enoicacid with pent-4-enoic acid; 2E/2F; 10H; saponification of the methylester with 1.0 M aqueous sodium hydroxide in methanol at 45° C.; and 1G.

TABLE I-17 Examples I-265 to I-334 HPLC LCMS RT (min.) Ex. # [M + H]⁺(Method) I-265

579.2 6.4  I-266

664.4 5.7  I-267

650.4 5.2  I-268

567.4 5.8  I-269

605.4 5.9  I-270

611.2 6.9  I-271

595.2 5.1  I-272

634.2 6.2  I-273

634.2 7.0  I-274

520.3 5.4  I-275

648.1 7.4  I-276

707.3 8.8  I-277

740.3 6.7  I-278

689.4 8.6  I-279

700.3 7.7  I-280

686.1 6.9  I-281

670.1 7.7  I-282

711.2 6.2  1-283

687.2 9.3  I-284

573.0 5.25 (D) 1-285

673.1 8.9  I-286

559.0 7.50 (D) I-287

606.1 5.55 I-288

700.1 7.16 I-289

715.2 5.35 I-290

700.1 7.01 I-291

700.1 7.00 I-292

736.1 6.87 I-293

714.2 7.01 I-294

748.1 7.77 I-295

686.1 8.01 I-296

702.2 7.42 I-297

706.2 8.45 I-298

700.2 7.75 I-299

633.1 5.50 I-300

688.1 7.93 I-301

713.1 9.13 I-302

687.1 7.87 I-303

681.1 8.89 I-304

737.0 7.68 I-305

680.3 7.07 I-306

707.0 9.92 I-307

544.0 6.8  I-308

615.9 7.1  I-309

554.0 7.4  I-310

542.0 6.9  I-311

639.9 8.3  I-312

570.0 4.5  I-313

549.0 3.5  I-314

549.0 6.5  I-315

545.0 4.2  I-316

680.2 7.44 I-317

644.0 6.61 I-318

644.0 6.37 I-319

592.9 6.41 I-320

607.0 6.67 I-321

545.0 3.61 I-322

545.0 3.75 I-323

544.9 5.37 I-324

568.9 7.38 I-325

622.9 6.05 I-326

631.0 7.09 I-327

590.0 9.21 I-328

633.0 8.21 I-329

562.0 6.05 I-330

665.0 8.97 I-331

575.9 8.01 I-332

666.1 6.02 I-333

527.1 4.51 I-334

513.1 3.88

Examples II-1 and II-2 were prepared in two steps by coupling 91A withan appropriately substituted carboxylic acid derivative (R—CO₂H) usingcoupling conditions described in step 15D, followed by aBoc-deprotection step as described in step 3C. Example II-3 was preparedby following the procedures described in step 3C, by replacing 3B with88G; followed by step 15D, by replacing Intermediate 2 with anappropriately substituted carboxylic acid; followed by Boc-deprotectionstep 3C. Examples II-4 and III-5 were prepared by coupling 96A with anappropriately substituted carboxylic acid derivative using couplingconditions described in step 15D. In the case of III-5 an additionalBoc-deprotection step as described in step 3C was required.

EXAMPLE II-6(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-5-carboxylic acid amide, TFA

II-6A. (S)-Benzyl 1-(4-chloropyridin-2-yl)but-3-enylcarbamate: 88B(1.135 g, 3.96 mmol) was taken up in MeOH (39.6 mL) and 4M HCl indioxane (19.79 mL, 79 mmol) was added. Reaction was stirred at rt underAr for ˜2 hrs then was evaporated to remove MeOH and triturated withEt₂O 2× to yield (S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine, 2 HCl(1.005 g, 99%, MS (ESI) m/z: 183.1 (M+H)⁺), which was taken up in MeOH(13.11 mL) and treated with benzyl 2,5-dioxopyrrolidin-1-yl carbonate(1.078 g, 4.33 mmol) and DIPEA (2.060 mL, 11.80 mmol). The resultingmixture was stirred at rt for 5 min then stripped to dryness, dilutedwith EtOAc and washed with brine, dried over MgSO₄, filtered, andevaporated. The residue was purified by flash chromatography to yieldII-6A (1.19 g, 96%) as a colorless oil. MS (ESI) m/z: 317.2 (M+H)⁺

II-6B. (S)-2-(1-(Benzyloxycarbonylamino)but-3-enyl)pyridin-4-ylboronicacid, TFA: A mixture of II-6A (0.75 g, 2.368 mmol), bis(neopentylglycolato)diboron (0.802 g, 3.55 mmol), potassium acetate (0.697 g, 7.10mmol), PdCl2(dppf)-CH₂Cl₂ adduct (1:1) (0.193 g, 0.237 mmol) and DMSO(7.89 mL) in a sealed tube was degassed by evacuating and backfillingwith Ar 3×, and then the reaction was heated at 80° C. for 6-8 h, thenleft at room temperature overnight. A second reaction was carried outidentically. The two reactions were combined and diluted with EtOAc,then filtered through a small pad of CELITE® which was rinsed severaltimes with EtOAc. The filtrate was transferred to a separatory funneland washed 3× with H₂O, refiltered again thru CELITE®, then washed withbrine, dried and concentrated to yield a dark brown oil which waspurified by reverse phase HPLC to yield II-6B as a white foam (1.325 g,63.6%). MS (ESI) m/z: 327.3 (M+H)⁺.

II-6C. (S)-Benzyl1-(4-(2-amino-4-cyanophenyl)pyridin-2-yl)but-3-enylcarbamate, 2 TFA: ToII-6B (0.44 g, 1.000 mmol), 3-amino-4-bromobenzonitrile (0.164 g, 0.833mmol) (81378-051-01), tetrabutylammonium bromide (0.013 g, 0.042 mmol),and 2M sodium carbonate (1.249 mL, 2.499 mmol) in a 20 mL microwave tubewas added toluene (6.92 mL) and EtOH (2.88 mL), and the solution wasdegassed by evacuating/flushing with Ar 3×. (Ph₃P)₄Pd (0.048 g, 0.042mmol) was added, and the vial was once again evacuated/flushed with Ar3×. Two more vials were prepared identically. All 3 vials were cappedand heated at 95° C. in an oil bath overnight. Then the reaction wasallowed to stir at rt for 3 days. Contents of vials were combined anddiluted with EtOAc and washed with water, sat. NaHCO₃, and brine, thendried over anhydrous magnesium sulfate, filtered, and evaporated.Residue was purified by flash chromatography to yield II-6C (0.758 g,48.4%) as a light yellow foam. MS (ESI) m/z: 399.3 (M+H)⁺.

II-6D.((E)-(S)-5-Cyano-9-oxo-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl)-carbamicacid benzyl ester: II-6D was prepared in two steps from II-6C using theprocedures described for steps 10D and 2E/F. MS (ESI) m/z: 439.2 (M+H)⁺.

II-6E.((E)-(S)-5-Carbamoyl-9-oxo-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl)-carbamicacid benzyl ester: II-6D (0.015 g, 0.034 mmol) (81378-069-01) wasdissolved in DMSO (0.171 mL) and K₂CO₃ (0.014 g, 0.103 mmol) was added.Then 30% H₂O₂(0.038 mL, 0.376 mmol) was added dropwise. The light yellowsuspension was stirred for ˜1 h at room temperature under nitrogen.Reaction mixture was diluted with water and extracted 3× with EtOAc. Theorganic layer was dried over MgSO₄, filtered, and condensed to yield thecrude amide as a colorless residue (0.022 g) which was taken on to thenext step without further purification. MS (ESI) m/z: 457.3 (M+H)⁺.

Example II-6. The title compound was prepared from II-6E using theprocedures described for steps 10F and 1G. ¹H NMR (500 MHz, CD₃OD) δ ppm9.49 (1 H, s) 8.76 (1 H, d, J=5.78 Hz) 8.00 (1 H, d, J=1.10 Hz)7.95-7.99 (2 H, m) 7.82 (1 H, dd, J=5.78, 1.65 Hz) 7.80 (1 H, d, J=1.65Hz) 7.77 (1 H, d, J=8.25 Hz) 7.66 (1 H, dd, J=8.39, 2.34 Hz) 7.57 (1 H,d, J=8.53 Hz) 7.10 (1 H, d, J=15.41 Hz) 6.79 (1 H, d, J=15.68 Hz) 5.12(1 H, dd, J=10.73, 5.78 Hz) 2.50 (1 H, ddd, J=12.52, 6.74, 1.93 Hz)2.07-2.19 (1 H, m) 1.93-2.01 (1 H, m) 1.82-1.92 (1 H, m) 1.70-1.80 (1 H,m) 1.60-1.69 (1 H, m) 1.33-1.42 (1 H, m) 0.71-0.86 (1 H, m). MS (ESI)m/z: 557.3 (M+H)⁺. Analytical HPLC: RT=4.95 min.

Example II-7 was prepared from 88B following the procedures describedfor steps II-6A, by replacing benzyl 2,5-dioxopyrrolidin-1-yl carbonatewith di-t-butyldicarbonate; 88C, by replacing 88B with(S)-2-(1-(tert-butoxycarbonylamino)but-3-enyl)pyridin-4-ylboronic acidand Intermediate 12 with methyl 4-amino-3-bromobenzoate; 10D; 2E/F; and2G; followed by hydrolysis of the methyl ester with 1M LiOH in THF; thensteps 3A and 1G. Example II-8 was similarly prepared following theprocedures described for steps II-6C, by substituting(S)-2-(1-(tert-butoxycarbonylamino)but-3-enyl)pyridin-4-ylboronic acidfor II6-B and 4-amino-3-bromobenzonitrile for3-amino-4-bromobenzonitrile; 10D, 2E/F, 3C and 1G.

EXAMPLE II-11{(E)-(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-trifluoromethyl-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

II-11A. (S)-tert-Butyl1-(4-(2-amino-4-nitrophenyl)pyridin-2-yl)but-3-enylcarbamate: CompoundII-11A was prepared by following the procedure described in step 88C, byreplacing 88B with (S)-tert-butyl1-(4-chloropyridin-2-yl)but-3-enylcarbamate. MS (ESI) 385.1 (M+H)⁺.

II-11B. (S)-tert-Butyl1-(4-(2,4-diaminophenyl)pyridin-2-yl)but-3-enylcarbamate: To a clear,orange solution of II-11A (2.9 g, 7.54 mmol) in methanol (75 mL) wasadded sequentially zinc dust (4.93 g, 75 mmol) and ammonium chloride(4.04 g, 75 mmol). The resulting suspension was stirred vigorously for 4h. The reaction was stopped and filtered through a 0.45 micron GMFeluting with methanol to give a clear, yellow filtrate. Concentration ofthe filtrate gave a yellow-black residue. The residue was partitionedbetween EtOAc and 0.25 M HCl (50 mL) and the layers were separated. Theorganic layer was extracted with 0.25 M HCl (1×50 mL). The combinedaqueous layers were basified with 1.5M K₂HPO₄ and then extracted withEtOAc (3×). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated to give II-11B (2.63 g, 98%) as abrown foam. MS (ESI) m/z: 355.2 (M+H)⁺.

II-11C.{3-Amino-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-pyridin-4-yl]-phenyl}-carbamicacid methyl ester: To a cooled (−78° C.) clear, brown solution of II-11B(2.63 g, 7.42 mmol) and pyridine (0.600 ml, 7.42 mmol) indichloromethane (74.2 ml) was added dropwise over 30 min methylchloroformate (0.516 ml, 6.68 mmol). The reaction was stirred at −78° C.After 1.5 h, the reaction was quenched with sat. NH₄Cl and the reactionwas allowed to warm to RT. The reaction was diluted with DCM and waterand the layers were separated. The aqueous layer was extracted with DCM(1×). The combined organic layers were washed with sat. NaHCO₃, brine,dried over Na₂SO₄, filtered and concentrated. The residue dissolved inDCM (˜10 mL) and then hexane (˜300 mL) was added to give a brownsuspension with brown gummy sticky substance at the bottom. The mixturewas sonicated to give a mostly clear solution with the brown substanceat the bottom. The solution decanted and the bottom substance rinsedwith hexane, dried to give II-11C (2.7 g, 88%) as a slightly brown foam.LCMS (ES) 413.2 (M+H)⁺.

II-11D.[4-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-pyridin-4-yl]-3-(1-ethoxy-2,2,2-trifluoro-ethylamino)-phenyl]-carbamicacid methyl ester: A clear yellow solution of II-11C (2.296 g, 5.57mmol), pTsOH (0.053 g, 0.278 mmol) and trifluoroacetaldehyde ethylhemiacetal (2.63 ml, 22.27 mmol) in ethanol (11.13 ml) was microwaved at120° C. for 3h. The reaction was concentrated, purified by normal phasechromatography which gave II-11D (1.61 g, 53.7%) as a yellow solid andas a mixture of diastereomers. MS (ESI) m/z: 539.2 (M+H)⁺.

II-11E.[4-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-pyridin-4-yl]-3-(1-trifluoromethyl-but-3-enylamino)-phenyl]-carbamicacid methyl ester: To a cooled (−20° C.) solution of II-11D (1.816 g,3.37 mmol) in THF (33.7 mL) was added dropwise allylmagnesium bromide(1M in Et₂O, 15.17 ml, 15.17 mmol). The resulting cloudy, red reactionmixture was stirred at −20° C. After 3h, another allylmagnesium bromide(0.8 mL, 0.8 mmol) added. After another 20 min, the reaction mixture wasquenched with sat. NH₄Cl and the reaction was warmed to RT. The reactionwas partitioned between water and EtOAc and the layers were separated.The aqueous layer was extracted with EtOAc (2×). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. Purification by normal phase chromatography gave II-11E(1.45 g, 80%) as a yellow foam and as a mixture of diastereomers. MS(ESI) m/z: 535.3 (M+H)⁺.

II-11F and II-11G.((E)-(S)-14-tert-Butoxycarbonylamino-9-trifluoromethyl-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-5-yl)-carbamic acid methyl ester: Compounds II-11F(diastereomer A) and II-11G (diastereomer B) were prepared following theprocedure described in 88G, by replacing 88F with II-11E. For II-11F: MS(ESI) m/z: 507.2 (M+H)⁺. For II-11G: MS (ESI) m/z: 507.3 (M+H)⁺.

II-11H. Example II-11 was prepared following the procedures described instep 3C, by replacing 3B with II-11F (diastereomer A); followed by step1G. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.51 (s, 1 H), 8.64 (d, J=5.5 Hz, 1H), 8.06 (d, J=1.1 Hz, 1 H), 7.98 (d, J=2.2 Hz, 1 H), 7.77 (dd, J=6.1,1.6 Hz, 1 H), 7.67 (dd, J=8.3, 2.2 Hz, 1 H), 7.58 (d, J=8.8 Hz, 1 H),7.33 (br. s., 1 H), 7.27 (d, J=8.2 Hz, 1 H), 7.09-7.18 (m, 2 H), 6.76(d, J=15.4 Hz, 1 H), 5.59-5.72 (m, 1 H), 5.06-5.24 (m, 2 H), 3.75 (s, 3H), 3.43-3.57 (m, 1 H), 2.83-2.94 (m, 1 H), 2.47-2.65 (m, 2 H),2.26-2.39 (m, 1 H). ¹⁹F NMR (471 MHz, CD₃OD) δ −75.49, −77.15. MS (ESI)m/z: 639.2 (M+H)⁺. Analytical HPLC, RT=6.74 min.

TABLE II-1 Examples II-1 to II-11 HPLC LCMS RT (min) Ex. # Structure[M + H]⁺ (method) II-1

508.2 6.5 (C) II-2

515.1 6.3 (C) II-3

513.1 6.3 (C) II-4

509.1 4.9 II-5

494.4 6.5 (C) II-6

557.3 5.0 II-7

558.2 5.2 II-8

515.2 4.1 (B) II-9

537.2 6.2 II-10

602.1 6.4 II-11

639.2 6.7

EXAMPLE II-12{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-trifluoromethyl-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl}-carbamic acid methyl ester, 2 TFA salt

II-12A.((S)-5-Methoxycarbonylamino-9-trifluoromethyl-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl)-carbamicacid tert-butyl ester: To the solution II-11F (diastereomer A) (0.46 g,0.908 mmol) in EtOH (6 mL) was added TFA (0.070 mL, 0.908 mmol) and 10%palladium on carbon (0.097 g, 0.091 mmol). Hydrogen, from a balloon, wasbubbled through the reaction for a few minutes, then the reaction wasstirred under H₂-balloon for 24 h. Additional TFA (0.070 mL, 0.908 mmol)was added, and the reaction was stirred under a H₂-balloon for another24 h. The reaction was filtered through 0.45 μm GMF rinsing with MeOH.The filtrate was concentrated. The residue was dissolved in EtOAc,washed with sat. NaHCO₃, brine, dried over Na₂SO₄, filtered andconcentrated. Purification by normal phase chromatography gave II-12A(0.4 g, 87% yield) as a yellow solid. MS (ESI) m/z: 509.3 (M+H)⁺.

II-12B.((S)-14-Amino-9-trifluoromethyl-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl)-carbamicacid methyl ester, 3 TFA salt: Compound II-12B was prepared followingthe procedure described in 3C, by replacing 3B with II-12A. MS (ESI)m/z: 409.1 (M+H)⁺.

II-12C. Example II-12 was prepared following the procedure described instep 1G by replacing 1F with II-12B. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.48(s, 1 H), 8.73 (d, J=1.4 Hz, 1 H), 8.66 (d, J=6.1 Hz, 1 H), 7.98 (d,J=2.2 Hz, 1 H), 7.89 (dd, J=6.2, 1.8 Hz, 1 H), 7.67 (dd, J=8.4, 2.3 Hz,1 H), 7.57 (d, J=8.5 Hz, 1 H), 7.48 (d, J=8.5 Hz, 1 H), 7.40 (d, J=1.7Hz, 1 H), 7.22 (dd, J=8.5, 1.9 Hz, 1 H), 7.11 (d, J=15.7 Hz, 1 H), 6.79(d, J=15.4 Hz, 1 H), 5.17 (dd, J=11.7, 6.5 Hz, 1 H), 3.76 (s, 3 H),2.95-3.05 (m, 1 H), 2.20-2.31 (m, 1 H), 1.84-1.99 (m, 2 H), 1.71-1.80(m, 1 H), 1.51-1.62 (m, 2 H), 1.41-1.50 (m, 1 H), 0.33-0.45 (m, 1 H).¹⁹F NMR (471 MHz, CD₃OD) δ −75.06, −77.30. MS (ESI) m/z: 641.3 (M+H)⁺.Analytical HPLC: RT=7.06 min.

Examples II-13 and II-14 were prepared in two steps by coupling II-12Bwith an appropriately substituted carboxylic acid derivative (R—CO₂H)using coupling conditions described in step 15D, followed by aBoc-deprotection step as described in step 3C.

Example II-15 were prepared according to the procedures described in11-12, by replacing II-11F with II-11G; followed by 11-14.

EXAMPLE II-17(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acrylamino]-5-methoxycarbonylamino-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-9-carboxylicacid ethyl ester, diastereomer A, 2 TFA salt

II-17A.2-{2-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-pyridin-4-yl]-5-methoxycarbonylamino-phenylamino}-pent-4-enoicacid ethyl ester: Compound II-17A was prepared following the proceduredescribed in I-67A, by replacing 10C with II-11C. MS (ESI) m/z: 539(M+H)⁺.

II-17B.(E)-(9R,14S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaene-9-carboxylicacid ethyl ester (diastereomer A) and II-17C.(E)-(9S,14S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,11,15,17-heptaene-9-carboxylicacid ethyl ester (diastereomer B): Compounds II-17B (diastereomer A) andII-17C (diastereomer B) were prepared following the procedure describedin 88G, by replacing 88F with II-17A. The diastereomers were separatedby chiral HPLC (OJ column, 20:20:60 EtOH:MeOH:heptane). For II-17B(diastereomer A): MS (ESI) m/z: 512, 511 (M+H)⁺. ¹H NMR (MeOH-d4, 400MHz): δ ppm 8.56 (d, 1H, J=5), 7.62 (s, 1H), 7.24 (d, 1H, J=5), 7.20 (d,1H, J=8), 7.03 (s, 1H), 6.98 (d, 1H, J=9), 5.44 (m, 1H), 5.07 (m, 1H),4.71 (m, 1H), 4.12 (q, 2H, J=7), 3.73 (s, 3H), 3.31 (m, 3H), 2.72 (m,1H), 2.35 (m, 4H), 1.44 (s, 9H), 1.20 (m, 3H). For II-17C (diastereomerB): MS (ESI) m/z: 512, 511 (M+H)⁺; ¹H NMR (MeOH-d4, 400 MHz): δ ppm 8.56(d, 1H, J=5), 7.49 (s, 1H), 7.21 (m, 2H), 6.99 (s, 1H), 6.94 (d, 1H,J=9), 5.66 (m, 1H), 5.03 (m, 1H), 4.12 (m, 3H), 3.72 (s, 3H), 3.31 (m,3H), 2.69 (m, 1H), 2.54 (m, 1H), 2.37 (m, 2H), 1.44 (s, 9H), 1.14 (t,3H, J=7).

II-17D.(9R,14S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-9-carboxylicacid ethyl ester: Compound II-17D was prepared following the proceduredescribed in II-12A, by replacing II-11F with II-17B (diastereomer A).MS (ESI) m/z: 514, 513 (M+H)⁺.

II-17E.(9R,14S)-14-Amino-5-methoxycarbonylamino-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,5,17-hexaene-9-carboxylicacid ethyl ester, 3HCl salt: A mixture of II-17D (175 mg, 0.341 mmol)and hydrogen chloride (1.71 ml, 6.83 mmol) (4 M in dioxane) and ethylacetate (2 mL) was stirred at room temperature for 1 h. Solvent wasremoved in vacuo to give a light tan yellow solid (130 mg): MS (ESI)m/z: 414, 413 (M+H)⁺. The product was taken on without furtherpurification.

II-17F. Example II-17 was prepared following the procedure described in1G, by replacing 1F with II-17E. MS (ESI) m/z: 647, 645 (M+H)⁺. ¹H NMR(MeOH-d4, 400 MHz): 9.49 (s, 1H), 8.79 (s, 1H), 8.64 (d, 1H, J=9), 7.97(d, 1H, J=2), 7.77 (d, 1H, J=9), 7.67 (dd, 1H, J=9, 2), 7.57 (d, 1H,J=9), 7.47 (d, 1H, J=8),7.38 (s, 1H), 7.23 (dd, 1H, J=9, 2), 7.11 (d,1H, J=15), 6.80 (d, 1H, J=15), 5.15 (m, 1H), 4.00 (m, 3H), 3.75 (s, 3H),3.31 (m, 1H), 3.08 (d, 1H, J=9), 2.20 (m, 2H), 1.94 (m, 2H), 1.77 (m,2H), 1.50 (m, 2H), 1.39 (m, 1H), 1.12 (t, 3H, J=7), 0.42 (m, 2H).

TABLE II-2 Examples II-12 to II-22

LCMS HPLC Ex. # R R³ [M + H]⁺ RT (min) II-12

CF₃ (from II-11F) 641.2 6.9 II-13

CF₃ (from II-11F) 548.4 4.8 II-14

CF₃ (from II-11F) 555.4 4.8 II-15

CF₃ (from II-11G) 555.3 3.9 II-16

H 573.3 6.2 II-17

645.4 6.5 II-18

645.4 6.1 II-19

617.4 5.7 II-20

637.5 7.0 II-21

602.5 7.1 II-22

663.4 6.9

EXAMPLE II-24(R)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-methoxycarbonylamino-18-oxo-8,16,17-triaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15-pentaene-9-carboxylicacid ethyl ester

II-24A. ((S)-3-tert-Butoxycarbonylamino-2-oxo-hex-5-enyl)-phosphonicacid dimethyl ester: To a solution of dimethyl methylphosphonate (6.99ml, 65.4 mmol) in THF (43.6 ml) at −78° C. was added BuLi (40.9 ml, 65.4mmol) slowly. After addition, the reaction was stirred for 40 min andthen a solution of (S)-methyl 2-(tert-butoxycarbonylamino)pent-4-enoate(3 g, 13.08 mmol) in THF (10 mL) was added dropwise. Stirring wascontinued for another 40 min at −78° C. The reaction was quenched byadding water, then EtOAc. It was washed with 1M HCl, sat NaHCO₃ andbrine. The organic phase was dried over MgSO₄, filtered and concentratedto give a clear oil. Purification by normal phase chromatography gaveII-24A as a colorless oil (4.19g, 99%). MS (ESI) m/z: 344.0 (M+Na)⁺.

II-24B. (4-Methoxycarbonylamino-2-nitro-phenyl)-oxo-acetic acid: To asolution of methyl 4-acetyl-3-nitrophenylcarbamate (10.5 g, 44.1 mmol)in pyridine (44.1 ml) was added selenium dioxide (7.34 g, 66.1 mmol) inportions. The reaction was stirred under argon at 60° C. overnight.Solvent was evaporated and pumped for several hours to remove mostpyridine. 1.0N HCl (60 mL) was added and the mixture was filtered,rinsed with 1N HCl. The solid was put in a vacuum-oven at 45° C.overnight. MeOH (200 mL) was added, filtered, the filtrate wasconcentrated to give 13.8g of II-24B as a brownish foam. MS (ESI) m/z:269.0, 223.0 (M+NH)⁺.

II-24C. (4-Methoxycarbonylamino-2-nitro-phenyl)-oxo-acetic acid methylester: To a red oil of II-24B (5 g, 16.03 mmol) in DCM (57.3 ml) at 0°C. was added TEA (3.13 ml, 22.45 mmol). The mixture was sonicated todissolve into a red-colored solution. Methyl carbonochloridate (1.739ml, 22.45 mmol) was added dropwise at 0° C. After 5 min, the reactionmixture was diluted with CH₂Cl₂ (100 mL), washed with 1M HCl, sat.NaHCO₃ and brine. The organic phase was dried over MgSO₄, filtered andconcentrated to give a red colored solid. Trituated with DCM and EtOAc,filtered. The solid was washed with DCM/Hex and dried in vacuum-oven at45° C. to give 2.79g (62%) of II-24C as a light brownish solid. MS (ESI)m/z: 223.0 (fragmentation).

II-24D.{4-[6-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-3-oxo-2,3-dihydro-pyridazin-4-yl]-3-nitro-phenyl}-carbamicacid methyl ester: To a clear solution of II-24A (911 mg, 2.84 mmol) inEtOH (30 ml) at rt were added potassium carbonate (588 mg, 4.25 mmol).The reaction mixture was stirred for 2 hr. The solvent was removed byrot-vap removed solvent and vacuum pump. THF (Volume: 30.0 ml) wasadded, followed by addition of II-24C. After 3 hrs, hydrazine (0.356 ml,11.34 mmol) was added and the rxn was stirred at rt for 3 days. Thereaction was diluted with EtOAc, washed with 1 N HCl, brine, dried overMgSO₄, filtered and concentrated. Purification by normal phasechromatography gave II-24D as a yellow foam (380 mg, 29%). MS (ESI) m/z:460.2 (M+NH)⁺.

II-24E.{4-[6-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-3-oxo-2,3-dihydro-pyridazin-4-yl]-3-amino-phenyl}-carbamicacid methyl ester: Example II-24E was prepared following the proceduresdescribed in 15B by replacing 15A with II-24D.

II-24F. Example II-24 was prepared following the procedures described inI-67A, by replacing 10C with II-24E; followed by procedures described insteps II-17B/II-17C; II-17D; II-17E; and II-17F. ¹H NMR (500 MHz, CD₃OD)δ 9.52 (s, 1H), 8.30 (s, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.78-7.65 (m, 1H),7.58 (d, J=8.5 Hz, 1H), 7.36 (d, J=1.9 Hz, 1H), 7.18-7.01 (m, 1H), 6.80(d, J=15.4 Hz, 1H), 5.03 (dd, J=11.4, 5.9 Hz, 1H), 4.14-3.92 (m, 2H),3.83-3.72 (m, 2H), 3.51-3.39 (m, 1H), 2.21-2.01 (m, 1H), 1.63-1.40 (m,2H), 1.15 (t, J=7.2 Hz, 2H), 0.96-0.81 (m, 1H). MS (ESI) m/z: 662.2(M+H)⁺.

Analytical HPLC: RT=9.81 min. (Method D).

EXAMPLE II-26(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acrylamino]-5-methoxycarbonylamino-8,17-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2(7),3,5,15,17-hexaene-9-carboxylicacid ethyl ester, diastereomer A, 2 TFA salt

II-26A.(R,E)-N-((5-Bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide:Example II-26A was prepared following the procedures described in 88A,by replacing 4-chloropicolinaldehyde with 5-bromonicotinaldehyde using(R)-2-methylpropane-2-sulfinamide. MS (ESI) m/z: 291.2 (M+H)⁺.

II-26B.(R)—N—((S)-1-(5-Bromopyridin-3-yl)but-3-enyl)-2-methylpropane-2-sulfinamide:Reference: Lin (Organic Letters, 10:1259 (2008)). To a sat. aq. solutionof sodium bromide (600 ml) was added powdered II-26A (8.3 g, 28.7 mmol)and indium (13.18 g, 115 mmol). Ally bromide (13.66 g, 115 mmol) wasadded via syringe pump, and the resulting light orange suspension wasallowed to stir at rt overnight, generating a beige foam. The reactionwas quenched with saturated aqueous NaHCO₃ and extracted with EtOAc. Theorganic layer was dried over anhydrous MgSO₄, filtered, concentrated togive a fluffy orange solid weighing 8 g. Purification by normal phasechromatography gave 4.25 g of II-26B as a beige solid. MS (ESI) m/z:333.0 (M+H)⁺.

II-26C. Example II-26 was prepared following the procedure described in88D, by replacing 88C with II-26B; followed by steps as described in88C; 88F; I-67A; 88G; 2G; II-17E; and 1G. ¹H NMR (500 MHz, CD₃OD) δ ppm9.49 (1 H, s), 9.36 (1 H, d, J=13.5 Hz), 8.76 (1 H, d, J=5.2 Hz), 8.54(1 H, br. s.), 7.97 (1 H, d, J=2.2 Hz), 7.66 (1 H, dd, J=8.5, 2.2 Hz),7.57 (1 H, d, J=8.5 Hz), 7.41 (1 H, d, J=8.5 Hz), 7.35 (1 H, s), 7.23 (1H, d, J=8.3 Hz), 7.11 (1 H, d, J=15.7 Hz), 6.75 (1 H, d, J=15.7 Hz),5.11-5.19 (1 H, m), 3.94-4.06 (2 H, m), 3.75 (3 H, s), 3.12 (1 H, d,J=11.6 Hz), 2.14-2.22 (1 H, m), 1.69-1.95 (3 H, m), 1.36-1.51 (3 H, m),1.11 (3 H, t, J=7.2 Hz), 0.57 (1 H, d, J=11.6 Hz) MS (ESI) m/z: 645.1(M+H)⁺. Analytical HPLC: RT=6.82 min. (Method D).

EXAMPLE II-28(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-methoxycarbonylamino-17-oxy-8,17-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaene-9-carboxylicacid ethyl ester, diastereomer A, TFA salt

II-28A. Example II-26 (15 mg, 0.017 mmol) was diluted with MeOH andfiltered through a cartridge of solid sodium bicarbonate to form thefree base. The filtrate was concentrated and to the resulting solid wasadded DCM (1 mL) and mCPBA (5.78 mg, 0.026 mmol). The solution wasstirred at rt for 1 h. The reaction mixture was washed with sat. Sodiumsulfite, sat. aq. NaHCO₃, and brine, then dried over MgSO₄. Filtered andconcentrated. Purification by reverse phase chromatography gave II-28(8.7 mg, 65%) as a pale yellow solid. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.49(1 H, s), 8.53 (1 H, s), 8.37 (1 H, s), 8.18 (1 H, s), 7.98 (1 H, d,J=2.2 Hz), 7.66 (1 H, dd, J=8.4, 2.3 Hz), 7.56 (1 H, d, J=8.5 Hz),7.27-7.39 (2 H, m), 7.05-7.22 (2 H, m), 6.73 (1 H, d, J=15.4 Hz),5.01-5.12 (1 H, m), 3.88-4.07 (2 H, m), 3.74 (3 H, s), 3.18 (1 H, dd,J=11.8, 1.4 Hz), 2.05-2.19 (1 H, m), 1.79-1.94 (1 H, m), 1.67-1.79 (2 H,m), 1.35-1.53 (3 H, m), 1.10 (3 H, t, J=7.0 Hz), 0.56-0.72 (1 H, m) MS(ESI) m/z: 661.3 (M+H)⁺. Analytical HPLC: RT=7.91 min. (Method D).

EXAMPLE II-29(9R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-methoxycarbonylamino-16-oxy-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaene-9-carboxylicacid ethyl ester, trifluoroacetic acid salt

II-29A.2-(tert-Butoxycarbonyl-{2-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-pyridin-4-yl]-5-methoxycarbonylamino-phenyl}-amino)-pent-4-enoicacid ethyl ester, di-hydrochloride salt: To a solution of Example II-17A(125 mg, 0.232 mmol) in dichloromethane (2.5 mL) was added DMAP (28.4mg, 0.232 mmol) and Boc₂O (0.119 mL, 0.511 mmol) followed by DIEA (0.101mL, 0.580 mmol). The reaction mixture was stirred at rt for 1.5h. Thereaction mixture is concentrated in vacuo, dissolved with ethyl acetateand washed with brine. The crude product is then purified using normalphase chromatography. MS (ESI) m/z: 639.

II-29B.(E)-(S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,11,15,17-heptaene-8,9-dicarboxylic acid 8-tert-butyl ester9-ethyl ester: This compound was prepared by the following the proceduredescribed for 88G, replacing 88F with II-29A. The compound as a mixtureof diastereomers was purified by reverse phase chromatography. MS (ESI)m/z: 611.

II-29C.(9R,14S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaene-8,9-dicarboxylic acid 8-tert-butyl ester 9-ethyl ester:This Example was prepared by the procedure used in II-12A, by replacingII-11F with II-29B. The diastereomers of Example II-29C were separatedby reverse phase chromatography. MS (ESI) m/z: 613 for both diastereomer1 (shorter retention time) and diastereomer 2 (longer retention time);each is a mono-trifluoroacetate salt.

II-29D.(9R,14S)-14-tert-Butoxycarbonylamino-5-methoxycarbonylamino-16-oxy-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaene-8,9-dicarboxylic acid 8-tert-butyl ester 9-ethyl ester: Toa solution of Example II-29C, diastereomer 2 (21 mg, 0.034 mmol) inethyl acetate was added a saturated solution of sodium carbonate inwater. After mixing, the layers were separated and the organic layer wasdried over magnesium sulfate. Filtration and removal of solvent in vacuogave the free base. This was then diluted with DCM (0.5 mL).m-Chloroperbenzoic acid (mCPBA) (11.52 mg, 0.051 mmol) was added. Thereaction mixture was stirred at RT. The reaction mixture is diluted withethyl acetate and washed with a saturated Na₂SO₃ solution, saturatedNaHCO₃ solution, then brine. The organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was used withoutany further purification. MS (ESI) m/z: 629.

II-29E.(9R,14S)-14-Amino-5-methoxycarbonylamino-16-oxy-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaene-9-carboxylicacid ethyl ester: Example II-29D was mixed with a solution of HCl indioxane and the reaction mixture was stirred at rt for 1 h. The reactionmixture was concentrated in vacuo and used as the di-hydrochloride saltfor the next step without any further purification. MS (ESI) m/z: 429.

Example II-29. Following the procedure used to make Example 1G,(E)-2,5-dioxopyrrolidin-1-yl3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylate (18 mg, 0.052 mmol) andII-29E (26 mg, 0.052 mmol) were dissolved in DMF (0.5 mL), and thenDIPEA (0.090 mL, 0.518 mmol) was added. The reaction mixture was stirredat room temperature under argon for 4h. The reaction mixture is dilutedwith ethyl acetate (10 mL) and washed with 10% LiCl solution. Dryingover Na₂SO₄, filtration and removal of solvent in vacuo gave the crudeproduct, which was purified by reverse phase chromatography. Solvent wasremoved in vacuo by lyophilization to give a solid (wt=9 mg, 21% yield):MS (ESI) m/z: 660.4; ¹H NMR (500 MHz, CD₃CN) δ 9.12 (s, 1H), 8.67 (d,J=6.0 Hz, 1H), 8.41-8.23 (m, 2H), 7.96-7.80 (m, 2H), 7.64-7.44 (m, 3H),7.32-7.21 (m, 2H), 7.11 (d, J=7.7 Hz, 1H), 6.97 (d, J=15.4 Hz, 1H), 6.75(d, J=15.4 Hz, 1H), 5.50-5.37 (m, 1H), 4.01-3.83 (m, 3H), 3.76-3.69 (m,4H), 2.95 (s, 1H), 2.32 (br. s., 1H), 1.95 (m, 1H) 1.92-1.72 (m, 1H),1.61 (br. s., 1H), 1.42 (br. s., 3H), 1.15-0.93 (m, 3H).

TABLE II-3 Examples II-23 to II-29

HPLC LCMS RT Ex. # x R7 [M + H]⁺ (min.) II-23

CO₂Et (diastereomer mixture) 662.2 9.5 II-24

CO₂Et (diastereomer mixture) 662.2 9.8 II-25

645.1 6.7 II-26

645.1 6.8 II-27

661.1 8.8 II-28

661.3 7.9 II-29

660.4 7.9

TABLE II-4 Examples II-30 to II-38

HPLC LCMS RT Ex. # R7 [M + H]⁺ (min.) II-30

617.1 6.9 II-31

631.3 7.6 II-32

656.3 7.0 II-33

686.2 6.4 II-34

670.2 6.5 II-35

699.2 6.0 II-36

701.5 5.0 II-37

707.2 5.8 II-38

688.1 9.9

EXAMPLE II-39(9S,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-(2-methoxy-ethoxycarbonylamino)-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaene-9-carboxylic acid ethyl ester,bis-trifluoroacetic acid salt

The synthesis of Example II-39 followed the general procedures describedfor 11-17. Example II-39AE (described below) was substituted forcompound II-17A. The diastereomers corresponding to Example II-17B,diastereomers A and B, were not separated. They were hydrogenated andthen separated by HPLC to give diastereomers corresponding to compoundII-17C and its diastereomer. The diastereomers were then separatelyconverted to Examples II-39 and II-40 (described below). The followingdata were collected for Example II-39: MS (ESI) m/z 689.3, 691.3; ¹H NMR(CD₃OD, 400 MHz): δ 9.37 (s, 1H), 8.55 (d, 1H, J=6), 8.28 (s, 1H), 7.87(d, 1H, J=2), 7.55 (dd, 1H, J=8, 2), 7.46 (d, 1H, J=8), 7.27 (d, 1H,J=8), 7.24 (d, 1H, J=2), 6.99 (d, 1H, J=16), 6.74 (d, 1H, J=16), 5.07(m, 1H), 4.17 (t, 2H, J=6), 3.94 (m, 2H), 3.55 (t, 2H, J=6), 3.29 (s,3H), 3.20 (m, 5H), 3.12 (m, 2H), 2.17 (m, 1H), 1.89 (m, 1H), 1.60 (m,2H), 1.40 (m, 4H), 1.03 (t, 3H, J=7), 0.58 (m, 1H).

II-39AA.((S)-1-{4-[4-Nitro-2-(2,2,2-trifluoro-acetylamino)-phenyl]-pyridin-2-yl}-but-3-enyl)-carbamicacid tert-butyl ester: To a solution of Example II-11A (0.40 g, 1.041mmol) in THF (Volume: 9 mL) at −78° C. was added Et₃N (0.435 mL, 3.12mmol), followed by (CF₃CO)₂O (0.154 mL, 1.093 mmol). The reactionmixture was warmed gradually to rt and stirred for 20.75 h. The reactionmixture was concentrated in vacuo. The residue was treated with water(10 mL) and extracted three times with EtOAc. The combined organics werewashed once with 1N HCl (3 mL), then dried over MgSO₄. Filtration,removal of solvent in vacuo and purification of the residue by normalphase chromatography provided an oil (Wt=239 mg): MS (ESI) m/z: 481.2.

II-39AB.((S)-1-{4-[4-Amino-2-(2,2,2-trifluoro-acetylamino)-phenyl]-pyridin-2-yl}-but-3-enyl)-carbamicacid tert-butyl ester: To a clear yellow solution of II-39AA (0.269 g,0.560 mmol) in MeOH (5.60 ml) was added sequentially zinc (0.366 g, 5.60mmol) and NH₄Cl (0.300 g, 5.60 mmol). The resulting suspension wasstirred vigorously for 6.5 h. The reaction mixture was filtered througha 0.45 micron GMF eluting with methanol to give a clear, yellowfiltrate. Concentration gave a dark yellow residue. The residue waspartitioned three times between EtOAc and 1 M HCl (10 mL) and the layerswere separated. The combined aqueous layers were basified with a 1 NNaOH solution (pH˜8 by paper) and then extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated to give an oil (Wt=200 mg): MS (ESI)m/z=451.3.

II-39AC.[4-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-pyridin-4-yl]-3-(2,2,2-trifluoro-acetylamino)-phenyl]-carbamicacid 2-methoxy-ethyl ester: A solution of II-39AB (200 mg, 0.444 mmol)and pyridine (0.180 mL, 2.220 mmol) in dichloromethane (4 mL) was cooledto 0° C. under argon with stirring. Then 2-methoxyethylcarbonochloridate (0.103 mL, 0.888 mmol) was added dropwise. Thereaction mixture was stirred for 50 min at 0° C. for 2 h. Added 50 μL ofthe chloroformate reagent and stirred at room temperature for 17.75 h.The reaction mixture was diluted with EtOAc and washed once with 2.2 mL1 N HCl, then twice with saturated Na₂CO₃ solution. The organic wasdried over MgSO₄ and filtered. Solvent was removed in vacuo to giveclear pale yellow oil (Wt=160 mg). MS (ESI) m/z=553.3. ¹H NMR (CD₃OD,500 MHz): δ 11.94 (s, 1H), 10.90 (s, 1H), 9.32 (d, 1H, J=5), 8.44 (s,1H), 8.36 (dd, 1H, J=10, 2), 8.20 (d, 1H, J=10), 8.17 (s, 1H), 8.01 (m,1H), 6.55 (m, 1H), 5.87 (d, 1H, J=17), 5.81 (d, 1H, J=9), 5.48 (M, 1H),5.15 (m, 1H), 5.06 (m, 2H), 4.67 (m, 2H), 3.31 (s, 3H), 3.23 (m, 1H).

II-39AD.{3-Amino-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-pyridin-4-yl]-phenyl}-carbamicacid 2-methoxy-ethyl ester: A mixture of Example II-39AC (160 mg, 0.290mmol), a 1M solution of LiOH in water (0.290 mL, 0.290 mmol) and THF 0.5mL) was stirred for ˜20 h. Added 0.2 mL 1M LiOH solution and continuedstirring for 24 h. A 1 N HCl solution (0.5 mL) was added and the mixturewas extracted three times with EtOAc. The organic layers were washedwith a saturated Na₂CO₃ solution, then dried over MgSO₄ and filtered.Solvent was removed in vacuo. The residue was purified by normal phasechromatography to provide a yellow oil (Wt=103 mg): MS (ESI) m/z=457(ES+) desired product.

II-39AE.2-[2-[2-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-pyridin-4-yl]-5-(2-methoxy-ethoxycarbonylamino)-phenylamino]-pent-4-enoicacid ethyl ester: The synthesis of Example II-39AE followed the generalprocedure described for II-17A where Example II-39AD was substituted forExample II-11C. The crude product was purified by normal phasechromatography to provide a yellow oil: MS (ESI) m/z=583.4 (ES+) desiredproduct.

EXAMPLE II-409R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-(2-methoxy-ethoxycarbonylamino)-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaene-9-carboxylic acid ethyl ester,bis-trifluoroacetic acid salt

The synthesis of Example II-40 followed the general procedures describedfor 11-17. Example II-39AE (described above) was substituted for ExampleII-17A. The diastereomers corresponding to Example II-17B, diastereomersA and B, were not separated. They were hydrogenated and then separatedby normal phase chromatography to give diastereomers corresponding toExample II-17C and its diastereomer. The diastereomers were thenseparately converted to Examples II-39 and II-40 (described below). Thefollowing data were collected for Example II-40: MS (ESI) m/z 689.3,691.3; ¹H NMR (CD₃OD, 400 MHz): δ 9.49 (s, 1H), 8.71 (s, 1H), 8.64 (d,1H, J=6), 7.99 (d, 1H, J=2), 7.72 (d, 1H, J=3), 7.67 (dd, 1H, J=8, 2),7.57 (d, 1H, J=9), 7.46 (d, 1H, J=9), 7.38 (d, 1H, J=2), 7.22 (dd, 1H,J=9, 2), 7.11 (d, 1H, J=16), 6.81 (d, 1H, J=16), 5.15 (dd, 1H, J=11, 5),4.28 (t, 2H, J=5), 4.00 (m, 2H), 3.66 (t, 2H, J=4), 3.40 (s, 3H), 3.30(m, 4H), 3.08 (d, 1H, J=11), 2.19 (m, 1H), 1.90 (m, 2H), 1.76 (m, 1H),1.49 (m, 2H), 1.38 (m, 1H), 1.09 (t, 3H, J=7), 0.37 (m, 1H).

EXAMPLE II-419R,14S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-5-(2-methoxy-ethoxycarbonylamino)-16-oxy-8,16-diaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaene-9-carboxylicacid ethyl ester, trifluoroacetic acid salt

This Example was prepared following the general procedures described forExample II-29.

II-41A (described below) was substituted for Example II-29A. Thefollowing data were collected for Example II-41. MS (ESI) m/z=705.3,707.3. ¹H NMR (CD₃CN, 500 MHz): δ 9.02 (s, 1H), 8.38 (d, 1H, J=8), 8.17(d, 1H, J=6), 7.85 (d, 1H, J=3), 7.75 (s, 1H), 7.51 (dd, 1H, J=11, 2),7.41 (d, 1H, J=8), 7.26 (d, 1H, J=3), 7.19 (d, 1H, J=8), 6.92 (d, 1H,J=16), 6.66 (d, 1H, J=16), 5.53 (m, 1H), 4.15 (t, 2H, J=6), 3.86 (m,2H), 3.49 (t, 2H, J=6), 3.25 (s, 3H), 2.97 (d, 1H, J=12), 2.38 (m, 5H),1.74 (m, 2H), 1.54 (m, 1H), 1.27 (m, 4H), 0.97 (t, 3H, J=7).

II-41A.2-{tert-Butoxycarbonyl-[2-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-pyridin-4-yl]-5-(2-methoxy-ethoxycarbonylamino)-phenyl]-amino}-pent-4-enoicacid ethyl ester: To a solution of Example II-39AE (83 mg, 0.142 mmol)in DCM (1.5 mL) was added DMAP (17.40 mg, 0.142 mmol) and Boc₂O (68.4mg, 0.313 mmol) followed by DIEA (0.062 mL, 0.356 mmol). The reactionmixture was stirred at rt for 3 h. The reaction mixture was concentratedin vacuo, dissolved with EtOAc and washed with brine. The crude productwas then purified by normal phase chromatography to give an oil (Wt=98mg): MS (ESI) m/z=681.3.

Compounds II-47 (diastereomer A) and II-48 (diastereomer B) wereprepared following the procedures described in amide coupling step 88E,by replacing 88D with II-11C and by replacing pent-4-enoic acid with2-methylbut-3-enoic acid; followed by ring-closing metathesis step 88G;hydrogenation step 2G where the diastereomers were separated by chiralprep hplc [Chiralcel OD, eluting with 80% isopropanol/heptane] to givediastereomer A and diastereomer B; Boc-deprotection step 3C; and 1G.

TABLE II-5 Examples II-39 to II-72 LCMS HPLC Ex. # [M + H]⁺ RT (min.)II-39

689.3  6.1  II-40

689.3  6.5  II-41

705.3  7.7  II-42

688.2 10.9  II-43

707.1  5.7  II-44

707.1  6.2  II-45

601.4 4.6/4.7 II-46

617.1  5.8  II-47 (Diastereomer A)

601.0  5.4  II-48 (Diastereomer B)

601.0  5.4  II-49

603.0  5.6  II-50

631.1  5.95 II-51

656.1  5.40 II-52

660.2  5.02 II-53

675.1  7.1  II-54

706.1  7.3  II-55

708.1  6.0  II-56

656.1  5.16 II-57

693.1  5.22 II-58

707.0  4.44 II-59

672.1  5.4  II-60

672.1  5.2  II-61

686.1  5.3  II-62

661.2  7.41 II-63

680.2 10.21 II-64

680.3 10.56 II-65

679.0  9.46  9.72 II-66

646.0  8.78 II-67

632.0  8.24 II-68

646.0  8.37 II-69

646.0  9.04 II-70

700.0  5.61 II-71

616.1  5.60 II-72

674.0  6.09

What is claimed is:
 1. A compound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, wherein: ring A is independently a C₃₋₁₀ carbocycle;ring B is pyridazine; ring C is independently a benzene ring or a 5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); L₁ is independentlyselected from the group consisting of: a bond, —CHR⁵—, —CHR⁵ CHR⁵—,—CR⁵═CR⁵—, —C≡C—, —OCH₂—, —CHR⁵ NH—, —CH₂O—, —SCH₂—, —SO₂CH₂—, —CH₂NH—,and —CR⁵R⁵—; L is independently selected from the group consisting of:C₃₋₈ alkylene, C₃₋₈ alkenylene, and C₄₋₈ alkynylene; wherein saidalkylene, alkenylene and alkynylene are substituted with 0-2 R⁷ andoptionally one or more of the carbon atoms of said alkylene andalkenylene may be replaced by O, S, NH, N(C₁₋₄ alkyl), CO, CONH, NHCO,OCONH, NHCO₂,—NHCONH—, SO₂NH, NHSO₂, CON(C₁₋₄ alkyl), or N(C₁₋₄alkyl)CO; Y is independently selected from the group consisting of: CH₂,CH(C₁₋₄ alkyl), C(C₁₋₄ alkyl)₂, CO, O, S, NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄alkyl)), —N(C₁₋₄ alkyl)CH₂—, —N(CO₂(C₁₋₄ alkyl))CH₂—, —N(CH₂CO₂(C₁₋₄alkyl))CH₂—, —CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—,—OCON(C₁₋₄ alkyl)-, —NHCONH—, —SO₂NH—, —NHCO₂—, and —NHSO₂—;alternatively, L-Y is —C₃₋₆ alkylene-CH═N—; R¹ is, independently at eachoccurrence, selected from the group consisting of: halogen, C₁₋₆ alkyl,C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, OH, OCH₂F, OCHF₂, OCF₃, CN,NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, CO₂(C₁₋₄ alkyl), CO(C₁₋₄ alkyl),—CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl), —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl),—NHCO₂(C₁₋₄ alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, and phenylsubstituted with 0-2 R^(a); R² is independently a 5- to 7-memberedheterocycle comprising carbon atoms and 1-4heteroatoms selected from N,NH, N(C₁₋₄ alkyl), O, and S(O)_(p), wherein said heterocycle issubstituted with 0-2 R^(2a); R^(2a) is, independently at eachoccurrence, selected from the group consisting of: halogen, C₁₋₄ alkyl,—CH₂OH, C₁₋₄ alkoxy, OH, CF₃, OCF₃, CN, NH₂, CO₂H, CO₂(C₁₋₄ alkyl),COC₁₋₄ alkyl, —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), and —SO₂N(C₁₋₄ alkyl)₂; R³ isindependently selected from the group consisting of: H, ═O, halogen, OH,NH₂, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, —CH₂OH, CO₂H, CO₂(C₁₋₄alkyl), —C(O)NH₂, —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, —CH₂CO₂H,and C₃₋₆ cycloalkyl; R⁴ is independently selected from the groupconsisting of: H, and C₁₋₄ alkyl; R⁵ is, independently at eachoccurrence, selected from the group consisting of: H, halogen, OH, andC₁₋₄ alkyl; R⁶ is, independently at each occurrence, selected from thegroup consisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄alkyl), —CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl),—NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂CH₂CH(C₁₋₄alkyl)O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂, —CONH(C₁₋₄ alkyl),—CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, and —NHCO₂(CH₂)₀₋₂R⁹; R⁷ is, independentlyat each occurrence, selected from the group consisting of: halogen, OH,NH₂, CH₂NH₂, C₁₋₄ haloalkyl, OCH₂F, OCHF₂, OCF₃, —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl),CH₂O(CH₂)₁₋₄O(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), CO₂(CH₂)₂O(C₁₋₄alkyl), CO₂(C₁₋₄ haloalkyl), CO₂(CH₂)₂SO₂(C₁₋₄ alkyl), CH₂CO₂H,CH₂CO₂(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, —OCO(C₁₋₄alkyl), —CH₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH(C₁₋₄ alkoxy), —CO₂(CH₂)₂O(C₁₋₄alkyl), —CO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —CONH(CH₂)₂O(C₁₋₄ alkyl),—CONH(CH₂)₂N(C₁₋₄ alkyl)₂, —CON(C₁₋₄ alkyl)(CH₂)₂O(C₁₋₄ alkyl),—CON(C₁₋₄ alkyl)(CH₂)₂N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl, —CONHBn, —CONH(OBn),—(CO)₀₋₁(CH₂)₀₋₃—C₃₋₆ carbocycle, and—(CH₂)₀₋₁—(CO)₀₋₁—(W)₀₋₁-(CH₂)₀₋₂—(4- to 6-membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C₁₋₄alkyl), O, and S(O)_(p)); wherein said carbocycle and heterocycle aresubstituted with 0-2 R⁸; R⁸ is, independently at each occurrence,selected from the group consisting of: halogen, OH, CHF₂, CF₃, C₁₋₄alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂, and C₁₋₄ alkyl; R⁹ is a 4-to 6-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)), O, and S(O)_(p);R^(a) is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, CF₃, C₁₋₄ alkoxy, and C₁₋₄ alkyl; W isindependently selected from the group consisting of: O, NH and N(C₁₋₄alkyl); and p is, independently at each occurrence, selected from thegroup consisting of: 0, 1, and
 2. 2. The compound of claim 1, wherein:ring A is independently a 6-membered carbocycle or a 9- to 10-memberedcarbocycle; and ring C is benzene.
 3. The compound of claim 2, wherein:ring A is benzene.
 4. The compound of claim 1, wherein: L₁ isindependently selected from the group consisting of: a bond, —CH₂CH₂—,—CH═CH—, —C(Me)═CH—, —C≡C—, and —CH₂NH— in Formula (I); L isindependently selected from the group consisting of: C₃₋₇ alkylene andC₃₋₇ alkenylene; wherein said alkylene and alkenylene are substitutedwith 0-2 R⁷ and optionally one or two of the carbon atoms of saidalkylene and alkenylene may be replaced by O, CO, NH, N(C₁₋₄ alkyl),CONH, NHCO, or CON(C₁₋₄ alkyl); Y is independently selected from thegroup consisting of: CH₂, CO, CH(C₁₋₄ alkyl), C(C₁₋₄ alkyl)₂, O, S, NH,N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)), —N(C₁₋₄ alkyl)CH₂—, —N(CO₂(C₁₋₄alkyl))CH₂—, —N(CH₂CO₂(C₁₋₄ alkyl))CH₂—, —CONH—, —NHCO—, —CONHCH₂—,—CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —NHCONH—, and —SO₂NH—; alternatively, L-Yis —(CH₂)₃₋₆—CH═N—; R¹ is, independently at each occurrence, selectedfrom: halogen, CN, OH, OCH₂F, OCHF₂, OCF₃, C₁₋₄ haloalkyl, C₁₋₄ alkyl,C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,—C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, and —SO₂NH₂; R³ is independently selectedfrom the group consisting of: H, halogen, OH, NH₂, CN, CF₃, C₁₋₄ alkyl,C₁₋₄ alkoxy, —CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄ alkyl)₂, —CH₂CO₂H, and C₃₋₆ cycloalkyl; and R⁶ is,independently at each occurrence, selected from the group consisting of:halogen, C₁₋₄alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl), —CH₂CO₂H,—(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂,—NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl),—NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl),—SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl),CON(C₁₋₄ alkyl)₂, —NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCOCF₃, and—NHCO₂(CH₂)₀₋₁R⁹.
 5. The compound of claim 1, wherein: L₁ isindependently selected from the group consisting of: a bond, —CH₂CH₂—and —CH═CH— in Formula (I); R¹ is, independently at each occurrence,selected from the group consisting of: halogen, CN, C₁₋₄ alkyl, OH, C₁₋₄alkoxy, CH₂F, CHF₂, CF₃, OCH₂F, OCHF₂, OCF₃, CO(C₁₋₄ alkyl), NH₂,NH(C₁₋₄ alkyl)₂, N(C₁₋₄ alkyl)₂, —CH₂NH₂, and —C(═NH)NH₂; R³ isindependently selected from the group consisting of: H, halogen, CN,CF₃, CO₂H, CO₂(C₁₋₄ alkyl), C₁₋₄ alkyl, CONH₂, CON(C₁₋₄ alkyl)₂, andC₃₋₆ cycloalkyl; and R⁶ is, independently at each occurrence, selectedfrom the group consisting of: halogen, C₁₋₄alkyl, CN, OH, CF₃, CO₂H,CO₂(C₁₋₄ alkyl), —CH₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄alkyl), —NHCO₂(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄ alkyl), —CONH₂, CONH(C₁₋₄alkyl), CON(C₁₋₄ alkyl)₂, —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂CH₂CO₂H, —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCOCF₃,


6. The compound of claim 1, wherein: L₁ is independently selected fromthe group consisting of: a bond and —CH═CH— in Formula (I); L isindependently selected from the group consisting of: —(CH₂)₃₋₆—,—(CH₂)₂₋₄CH(C₁₋₄ alkyl)(CH₂)₀₋₂—, —(CH₂)₁₋₂—CH═CH—(CH₂)₀₋₃—,—CH₂—CH═C(C₁₋₄ alkyl)-(CH₂)₁₋₂—, —CH₂—C(C₁₋₄ alkyl)═CH—(CH₂)₁₋₂—,—CH₂—CH═CH—CH₂CH(C₁₋₄ alkyl)-, —CH₂—CH═CH—CH(C₁₋₄ alkyl)-(CH₂)₀₋₂—,—CH₂—CH═CH—CH₂C(halo)₂-, —CH₂—CH═CH—(CH₂)₁₋₂CH(CF₃)—,—CH₂—CH═CH—CH(OH)CH₂—, —(CH₂)₃CH(halo)-, —(CH₂)₃₋₄C(halo)₂-,—(CH₂)₄CH(CH₂OH)—, —(CH₂)₃₋₄CH(C₁₋₄ alkoxy)-, —(CH₂)₄CH(CH₂(C₁₋₄alkoxy))-, —(CH₂)₄CH(CO₂H)—, —(CH₂)₄CH(CH₂CO₂H)—, —(CH₂)₄₋₅CH(CO₂(C₁₋₄alkyl))-, —(CH₂)₄CH(CH₂CO₂(C₁₋₄ alkyl))-, —(CH₂)₄CH(CO₂CH₂CF₃)—,—(CH₂)₄CH(CO₂(CH₂)₂SO₂(C₁₋₄ alkyl))-, —(CH₂)₄C(C₁₋₄ alkyl)(CO₂(C₁₋₄alkyl))-, —(CH₂)₄C(CF₃)(CO₂(C₁₋₄ alkyl))-, —(CH₂)₄CH(CONH₂))—,—(CH₂)₄CH(CONH(C₁₋₄ alkyl))-, —(CH₂)₄CH(CON(C₁₋₄ alkyl)₂)-,—(CH₂)₃CH(C₁₋₄ alkyl)CH(CONH₂)—, —(CH₂)₄CH(CO₂(CH₂)₂O(C₁₋₄ alkyl))-,—(CH₂)₄CH(CH₂NH(CH₂)₂O(C₁₋₄ alkyl))-, —(CH₂)₄CH(CONH(C₁₋₄ alkoxy))-,—(CH₂)₄CH(CONH(OBn))-, —(CH₂)₄CH((CH₂)₃Ph)-, —(CH₂)₄CH(CO₂(CH₂)₂N(C₁₋₄alkyl)₂)-, —(CH₂)₄CH(CONH(CH₂)₂O(C₁₋₄ alkyl))-,—(CH₂)₄CH(CONH(CH₂)₂N(C₁₋₄ alkyl)₂)-, —(CH₂)₄CH(CON(C₁₋₄alkyl)(CH₂)₂O(C₁₋₄ alkyl))-, —(CH₂)₄CH(CON(C₁₋₄ alkyl)(CH₂)₂N(C₁₋₄alkyl)₂)-, —(CH₂)₄CH(CH(halo)₂)-, —(CH₂)₄₋₅CH(CF₃)—,—(CH₂)₃C(halo)₂CH₂—, —(CH₂)₁₋₃CH(OH)(CH₂)₁₋₂—, —CH₂CH(OH)CH(OH)CH₂—,—(CH₂)₃CH(OCO(C₁₋₄ alkyl))CH₂—, —(CH₂)₃C(O)CH₂—, —CH₂O(CH₂)₂₋₄—,—CH₂NH(CH₂)₂₋₄—, —(CH₂)₂₋₃NH(CH₂)₁₋₂——(CH₂)₂₋₄N(C₁₋₄ alkyl)(CH₂)₀₋₂—,—CH₂CONH(CH₂)₂₋₄—, —CH₂CON(C₁₋₄ alkyl)(CH₂)₂₋₄—, —CH₂NHCOC(halo)₂CH₂—,—(CH₂)₄CH(3-C₁₋₄ alkyl-oxetan-3-yl)-, —(CH₂)₄CH(thiazol-4-yl)-,—(CH₂)₄CH(4-C₁₋₄ alkyl-thiazol-2-yl)-, —(CH₂)₄CH(1-C₁₋₄alkyl-imidazol-2-yl)-, —(CH₂)₄CH(1-C₁₋₄ alkyl-pyrazol-3-yl)-,—(CH₂)₄CH(1-C₁₋₄ alkyl-pyrazol-5-yl)-, —CH₂—CH═CH—CH₂CH(1-C₁₋₄alkyl-pyrazol-5-yl)-, —(CH₂)₄CH(1-C₁₋₄ alkyl-3-C₁₋₄alkyl-pyrazol-5-yl)-, —(CH₂)₄CH(1-C₁₋₄ alkyl-4-halo-pyrazol-3-yl)-,

Y is independently selected from the group consisting of: CH₂, CO, O,NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)), —N(C₁₋₄ alkyl)CH₂—, —N(CO₂(C₁₋₄alkyl))CH₂—, —N(CH₂CO₂(C₁₋₄ alkyl))CH₂—, —CONH—, —NHCO—, —CONHCH₂—,—CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —NHCONH—, and —SO₂NH—; and alternatively,L-Y is —(CH₂)₃₋₆—CH═N—; R¹ is, independently at each occurrence,selected from the group consisting of: halogen, C₁₋₄alkyl, OH, C₁₋₄alkoxy, CO(C₁₋₄ alkyl), CN, CH₂F, CHF₂, CF₃, OCHF₂, NH₂, N(C₁₋₄ alkyl)₂,—CH₂NH₂, and —C(═NH)NH₂; R³ is independently selected from the groupconsisting of: H, halogen, C₁₋₄ alkyl, CN, CO₂(C₁₋₄ alkyl), CONH₂,CON(C₁₋₄ alkyl)₂, and C₃₋₆ cycloalkyl; and R⁶ is, independently at eachoccurrence, selected from the group consisting of: halogen, NH₂, CO₂H,CO₂(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, —NHCO₂(C₁₋₄alkyl), —CH₂NHCO₂(C₁₋₄ alkyl), —NHCO₂CH₂CO₂H, —NHCO₂(CH₂)₂OH,—NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl),—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCOCF₃,


7. A pharmaceutical composition comprising one or more compounds ofclaim 1 and a pharmaceutically acceptable carrier or diluent.
 8. Amethod for the treatment of a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound of claim 1, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof.
 9. A compound selected fromthe group consisting of